Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 7-Day Trial for You or Your Team.

Learn More →

Role of the NFκB-signaling pathway in cancer

Role of the NFκB-signaling pathway in cancer Journal name: OncoTargets and Therapy Article Designation: Review Year: 2018 Volume: 11 Running head verso: Xia et al OncoTargets and Therapy Dovepress Running head recto: NFκB pathway in cancer open access to scientific and medical research DOI: 161109 Open Access Full Text Article Review 1, Longzheng Xia * Abstract: Cancer is a group of cells that malignantly grow and proliferate uncontrollably. 1, At present, treatment modes for cancer mainly comprise surgery, chemotherapy, radiotherapy, Shiming Tan * molecularly targeted therapy, gene therapy, and immunotherapy. However, the curative effects Yujuan Zhou of these treatments have been limited thus far by specific characteristics of tumors. Abnormal Jingguan Lin 1 activation of signaling pathways is involved in tumor pathogenesis and plays critical roles in Heran w ang growth, progression, and relapse of cancers. Targeted therapies against effectors in oncogenic Linda Oyang signaling have improved the outcomes of cancer patients. NFκB is an important signaling Yutong Tian pathway involved in pathogenesis and treatment of cancers. Excessive activation of the NFκB- Lu Liu signaling pathway has been documented in various tumor tissues, and studies on this signaling Min Su pathway for targeted cancer therapy have become a hot topic. In this review, we update current Hui w ang understanding of the NFκB-signaling pathway in cancer. 1,2 Deliang Cao Keywords: nuclear factor kappa-B, p65, signaling pathway, cancer, inflammation Qianjin Liao Hunan Key Laboratory of Introduction Translational Radiation Oncology, Malignant tumors have become one of the most deadly diseases and a prominent Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School public health problem threatening human lives around the world. In recent years, of Medicine, Changsha, Hunan, China; 2 with social and economic development, as well as aging of the population, the inci- Department of Medical Microbiology, immunology, and Cell Biology, dence and mortality of cancer are increasing. The overall incidence of common Simmons Cancer institute, Southern malignant tumors will rise from 14 million in 2012 to a predicted 19 million in 2025 illinois University School of Medicine, 3,4 Springfield, iL, USA and 24 million in 2035, according to the World Health Organization. Cancer occurs due to oncogene activation, tumor-suppressor gene inactivation, loss of control of the *These authors contributed equally to this work 5 cell cycle, genomic instability, telomerase loss, and resistance of apoptosis. However, the specific pathogenesis of cancer varies with types of cancers. The cell-signaling pathway is the process by which cell responds to stimuli of extracellular signaling molecules that bind to receptors located on the cell membrane or in the cytoplasm of cells. This binding to receptors transfers signals to the nucleus and induces corresponding gene expression, thus producing biological effects and 6 7,8 cellular responses. In tumorigenesis, signaling pathways are less controlled. Abnormal regulation and cross-talk of cell-signal-transduction pathways play a Correspondence: Qianjin Liao; key role in cancer, and obstruction of or anomalies in signaling pathways may Deliang Cao Hunan Key Laboratory of Translational lead to excessive cell proliferation, apoptotic resistance, angiogenesis, invasion, Radiation Oncology, Hunan Cancer and metastasis, leading to development and progression of cancer. NFκB is an Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central important signaling pathway that is involved extensively in cancer development and South University, 283 Tongzipo Road, progression. Through controlling the expression of target genes, such as TNFA, IL6, Changsha, Hunan 410013, China Tel +86 731 8865 1681 BCLXL, BCL2, BCLXS, XIAP, and VEGF, NFκB mediates tumor-cell proliferation, Fax +86 731 8865 1999 survival, and angiogenesis. This review focuses on this NFκB-signaling pathway email [email protected]; [email protected] in tumors. submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 2063–2073 Dovepress © 2018 Xia et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/OTT.S161109 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Xia et al Dovepress Overview of NFκB-signaling present in cells in the form of their precursors. In these members, RelB can form dimers only with p50 or p52, but pathways others can form either homologous or heterologous dimers. Proteins and structure of NFκB family However, the most common NFκB dimer is the heterodimer NFκB is an important transcription-factor family of five of p65–p50. These homologous and/or heterologous dim- subunits: Rel (cRel), p65 (RelA, NFκB3), RelB, p105/p50 ers can bind to a specific sequence (ie, NF κB sites) of the 10–12 (NFκB1), and p100/p52 (NFκB2). Among these, p65, target gene to regulate gene transcription. Therefore, NFκB cRel, and RelB contain an N-terminal Rel-homologous regulates the activity of cells through the slight difference in domain (RHD; about 300 amino acids) and a C-terminal binding of these NFκB dimers to targeted sequences. 13,14 transactivation domain (TAD; Figure 1), while p50 and 15,16 p52 have only an RHD, but not a TAD. The C-terminal of p100 and p105 contains ankyrin repeats that function as iκBs and iKKs a p52 and p50 inhibitor. The RHD is responsible for DNA IκBs and IKKs are upstream regulators of the NFκB- binding and dimerization between different or identical signaling pathway. In cells that are not stimulated, NFκB family members, including the nuclear localization sequence dimers are present in an inactive state by binding to three and IκB-binding region, leading to homomeric or hetero- inhibitory factors (IκBα, IκBβ, and IκBε) of the NFκB in the meric binding of the subunits. The TAD is associated only cytoplasm, which blocks the nuclear localization sequence 18 20,21 with transcriptional activation. Therefore, the p50–p52 and prevents the NFκB from transition into the nucleus. homologous dimer does not activate gene transcription, but In addition, there are also two precursor IκBs: p105/IκBγ acts as an inhibitory molecule. Both p50 and p52 are usually and p100/IκBδ. IκBα specifically inhibits the p50/RelA 71)αSURLQIODPPDWRU\F\WRNLQHV β5&'%5%$))5 OLSLGSRO\VDFFKDULGHVJURZWK 5$1. IDFWRUVDQGDQWLJHQV &HOOUHFHSWRU &HOOUHFHSWRU ,..α ,..β 5HO% ,κ%α ,..γ β7 U&3 S 1,. 8E ,..α 8E 8E S S ,κ%α ,κ%α 5HO% 5HO% S S S 8E 5HO% 1XFOHXV '1$ ELQGLQJDQGJHQHWUDQVFULSWLRQ Figure 1 Structure of NFκB members. Notes: The NFκB family consists of three proteins with a transactivation domain (RelA [p65], cRel, and RelB) and two proteins lacking a transactivation domain (p105/p50 and p100/p52). Similarly, only p105/p50 and p100/p52 have ankyrin repeats that function as p52 and p50 inhibitors. However, all these proteins share an Rel-homology domain, associated with DNA binding, dimerization, nuclear localization and iκB binding, and nuclear localization signal exposure, which is vital to the translocation of the dimer into the nucleus. Abbreviation: NiK, NFκB-inducing kinase. submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 Dovepress /7 Dovepress NFκB pathway in cancer heterodimer, IκBβ targets the RelA/cRel heterodimer, and phosphorylation speed of the same IKK for IκBα and IκBβ IκBε inhibits the RelA and cRel dimers. Although different are different. IKKβ has stronger affinity for I κBα than IκBβ. external stimuli cause differential activation of NFκB through Also, the IκB-kinase complex can phosphorylate the NFκB- different IκBs, almost all known NFκB agonists can rap- bound IκB protein and contribute to proteasomal degradation 26 32 idly and transiently activate NFκB by degradation of IκBs. of the IκB protein faster. The IκB proteins p105/IκBγ and p100/IκBδ play a dual role, ie, precursors of the NFκB proteins p50 and p52 and inhibi- Activation of NFκB-signaling pathway tors of NFκB signaling. Different external stimuli have In a resting status of cells, complexes formed from NFκB differential effects on the different subunits of IκBs, leading and IκB (NFκB–IκBα or NFκB–IκBε) shuttle between the to differential activation of the NFκB pathway. cytoplasm and nucleus in a dynamic equilibrium. When cells The IKK (IκB kinase) complex consists of the catalytic are stimulated by extracellular signals, such as TNFα, IL1, subunits IKKα and IKKβ and the regulatory subunit NFκB lipopolysaccharide, viral double-stranded RNA, and ionizing essential modifier (NEMO; also called IKK γ). The IKKs radiation, NFκB is activated and enters the nucleus to bind to 28 34–39 are upstream regulators of IκBs. Both IKKα and IKKβ target genes. Upon activation, NFκB-signaling pathways subunits have about 52% of the sequence identity, but play are classified as canonical or noncanonical (Figure 2). The a key but divergent role in regulation of global NFκB- common regulatory step in both pathways is activation of the signaling activity. NEMO contains several domains that IKK complex. The IKK complex is phosphorylated, and in are crucial for its function as a regulatory subunit of the turn induces phosphorylation of IκB proteins IκBα or IκBβ, canonical IKK complex. The N-terminal coiled-coil domain leading to ubiquitination and degradation by proteasomes. of NEMO interacts with IKKα and IKKβ. Different IKKs Similarly, p100 and p105 are phosphorylated and cleaved demonstrate differential strength and speed for different into maturated p52 and p50 upon IKK activation. Therefore, substrates. IKKα is mainly the specific upstream kinase of NFκB dimers are released from their inhibitors and free to IκBβ and can strongly phosphorylate the Ser23 of IκBβ, but translocate into the nucleus to regulate expression of their not the Ser19. This inequivalent phosphorylation of Ser23 target genes. and Ser19 in IκBβ leads to degradation of IκBβ. IKKβ can The canonical NFκB-transcription factor is an inactive specifically phosphorylate the Ser sites of I κBα and IκBβ, dimer composed of a p50 and RelA/p65 subunit, which and the intensity is 20 times that of IKKα. In addition, the largely resides in the cytoplasm as part of a latent complex 5HOKRPRORJRXV $QN\ULQ GRPDLQ SS 5+' 1/6 SS 5+' 1/6 ,QWHUGRPDLQOLQNHU 1/6SRO\SHSWLGH 7 UDQVDFWLYDWLRQGRPDLQ 5HO$  S 5+' 1/6 ' 5HO% 5+' 1/6 ' F5HO 5+' 1/6 ' Figure 2 Activation of NFκB cascade by the classical/canonical signaling pathway (right) and alternative/noncanonical signaling pathway (left). Abbreviations: NLS, nuclear localization sequence; RHD, Rel-homologous domain; TAD, transactivation domain. submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 Dovepress 7$ 7$ 7$ Xia et al Dovepress 41,42 with IκBα under basal conditions. The formation of p65 Ubiquitination, a PTM of addition of ubiquitin (Ub) (RelA)–p50 or p65–cRel heterodimers is a key to activation. moieties to a protein, is the primary mechanism of protein Stimulation by proinflammatory cytokines, such as TNF α, turnover in the cell, and is recognized as the “traditional” IL1β, TLR ligands, and T-cell-receptor activators, results function of Ub tagging. Ub moieties on NFκB-signaling in activation of the IKKβ complex, and then IκBα is phos- proteins can serve as a docking platform for other proteins 44,45 72 phorylated at Ser32 and Ser36 by the IKK complex, with specific Ub-binding domains. First, the Ub moiety is 46–49 polyubiquitinated at K63, and degraded by proteasomes. activated by the E1 Ub-activating enzyme. Following acti- Degradation of IκBα consequently releases the canonical vation, one of several E2 Ub-conjugating enzymes transfers NFκB dimer p50-RelA/p65 to translocate into the nucleus Ub from E1 to several E3 enzymes (Ub ligases), to which and activate gene transcription. the substrate protein is specifically bound. The Ub moiety Although the canonical NFκB pathway has been more includes seven lysine (K) residues (K6, K11, K27, K29, K33, extensively studied, it is not to be ignored that the nonca- K48, and K63) and a methionine at the N-terminus (M1), nonical pathway (or alternative NFκB pathway) is vital in which can link another Ub to form a polyUb chain. some aspects. This alternative pathway is activated by TNF- Ub signaling controls activation of NFκB and innate receptor (TNFR) family members, such as LTβR, BAFFR, immunoresponses downstream of pattern-recognition recep- 52–56 RANK, and CD40. Once the receptor is activated, TRAF tors, such as Toll-like receptors, nucleotide-oligomerization proteins are able to mediate the activity of NFκB-inducing domain-like receptors, and cytokine receptors, eg, TNFR1, in 57,58 74–76 kinase and activate an IKKα homodimer at the same time, normal intestinal epithelial cells and colon cancer cells. ultimately leading to heterodimerization of the p100 precur- K48-linked polyubiquitination is a key step in releasing sor with RelB and processing into the active p52 subunit. NFκB from IκBs in the canonical pathway and processing of This processing of p100 induces the generation of the non- p100/102 into p52/50 in the noncanonical pathway to activate canonical transcription factor, a p52-RelB dimer, which then the NFκB pathway in inflammatory diseases, autoimmune 70,77,78 binds to κB DNA-binding sites and controls expression of diseases, and cancers. The Skp1–Cullin–F-box (SCF)– targeted genes. Therefore, activation of these two pathways βTrCP complex catalyzes the K48-linked polyubiquitination is achieved by phosphorylation of IκB proteins, which relieve of IκBα at two N-terminal lysine residues (K21 and K22), the inhibition of IκB proteins to NFκB dimers. inducing 26S proteasome-dependent degradation of IκBα and nuclear translocation of canonical NFκB. In addition, the Posttranslational modifications of phosphorylation of IκBα induced by NFκB-inducing kinase NFκB proteins could cause the phosphorylation of p100 on the C-terminal NFκB has hundreds of validated transcriptional targets, region (Ser866 and Ser870) and polyubiquitination of p100 and thus NFκB-signaling activity is under stringent spatial by the SCF–βTrCP–E3 ligase complex to regulate the activity and temporal control at the levels of nuclear transloca- of the noncanonical NFκB. The IKKβ subunit is also tion and posttranslational modic fi ations (PTMs) of signaling polyubiquitinated by a K63-linked chain in human cervical 61,62 79 components. There is a wide range of PTMs of NFκB HeLa cells. Importantly, activation of IKK is essential to subunits, and PTMs provide essential mechanisms differ- productive signaling and NFκB-mediated transcription, and entially to regulate NFκB-signaling activity in response to its activation depends on the binding of Met1-Ub by the IKK the various stimuli that activate this pathway in many cancer subunit NEMO. 64,65 cells. Although these modifications have a critical role Phosphorylation is critical for NFκB activity, including in the normal and pathological functions of NFκB in vivo, binding to and transcription of genes that contain a con- the physiological significance of PTMs remains unclear in sensus sequence. Phosphorylation of key NFκB-signaling cancer cells. PTMs not only can contribute to the control molecules often positively mediates signal transduction by of nuclear translocation but also have an important inu fl ence inducing protein conformational changes in breast cancer 82,83 in functions of NFκB subunits, including protein degrada- cell lines. Activation of NFκB signaling is involved in a 67–69 tion, DNA binding, and transcriptional activity. PTMs of series of phosphorylation events of upstream NFκB regula- NFκB include phosphorylation, ubiquitination, acetylation, tors and NFκB family members. In fact, the activity of NFκB and methylation. Herein, we focus on the ubiquitination, is controlled to a great extent by phosphorylation of RelA or phosphorylation, and methylation of the functional subunits upstream regulators in esophageal squamous-cell carcinoma, 81,84 of NFκB. gastric cancer, and oral cancer. The main subunit RelA of submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 Dovepress Dovepress NFκB pathway in cancer NFκB is targeted for phosphorylation at many phosphoac- of K37 and K218/221 on NFκB is able to constitute “bar ceptor sites within both the RHD (Ser205, Ser276, Ser281, codes” that guide differential activation of NFκB, binding Ser311, and Thr254) and TAD (Ser468, Ser529, Ser535, to specific promoters. Ser536, Thr435, and Thr505). For example, the phospho- rylation of Ser536 induced in the cytoplasm can increase Roles of NFκB in cancer NFκB transcriptional activity, while phosphorylation of At present, the role of the NFκB-signaling pathway in cell Ser529 increases DNA binding and oligomerization in biogenic activities is the hot spot of cancer research. NFκB laryngeal cancer cells. The phosphorylation of Ser536 signaling is involved in cellular immunity, ina fl mmation, and results in nuclear accumulation of RelA through disruption stress, as well as regulation of cell differentiation, prolifera- 97–101 of the cytoplasmic/nuclear shuttling of NFκB–IκBα com- tion, and apoptosis. The NFκB pathway is often altered plexes. In addition, phosphorylation of Ser276 can promote in both solid and hematopoietic malignancies, promoting 52,102,103 RelA interaction with the transcriptional coactivator CBP/ tumor-cell proliferation and survival. However, recent p300. Meanwhile, p-Ser276 RelA facilitates recruitment of evidence indicates that NFκB plays a tumor-suppressive role DNMT1/DNA (cytosine 5)–methyltransferase 1 to chromatin in certain cancers through transcriptional activation of the and subsequent BRMS1-promoter methylation and tran- Fas ligand. scriptional repression in human NSCLC cells. In addition, Pro- and anti-inflammatory effects of phosphorylation of IκBs is a key step of their proteasomal degradation and the release of NFκB for nuclear translocation NFκB and activation of gene transcription. Cytokines in the tumor The pathogenic role of inflammation in cancer has drawn microenvironment, such as TNFα, could bind to the cell- intensive research and highlighted the context-dependent surface TNF receptor, causing TNF-receptor multimerization modulation of inflammation-associated cancer by the tran - 87,88 105 and interacting with TRADD in the cytoplasm. TRADD scription factor NFκB. Through control of inflammatory 89 90 recruits TRAF and kinase RIP. Then, the stimulated responses, NFκB has influence in tumor development and signals are transmitted to IKK by RIP, which can make the progression by excessive innate immunity activation and Ser32 and Ser36 residues in α-subunits of IκB and Ser19 abnormal cell growth. Ina fl mmation-associated cancer can 91,92 and Ser23 residues in β-subunits of IκB phosphorylated. secrete various cytokines and chemokines through NFκB Then, IκB protein is dissociated from the p50-p65-IκB trimer binding to the promoters of genes, such as IL1B, TNF, and and subsequently degraded by proteasomes, activating the IL6. At the same time, activation of NFκB can be regulated 77 108,109 NFκB pathway. by the TNFα-receptor family, including RANKL. In recent years, accumulated evidence has suggested that It is well known that ina fl mmatory gene signatures are histone-modifying enzymes not only modify histone proteins altered in various tumor-cell lines and specimens of differ- but also play a role in the modic fi ation of nonhistone proteins, ent histological and molecular subtypes. Researchers have such as NFκB. NFκB can be methylated reversibly on lysine found that the inflammatory genes, such as IL1, IL6, IL8, or arginine residues by histone-modifying enzymes, including and CCL2, are also actively expressed in glioma-cell lines, lysine and arginine methyl transferases and demethylases. playing differential and cooperative roles in promoting prolif- The methylations of both lysine and arginine occur mainly eration, invasion, angiogenesis, and macrophage polarization 94,95 110 on the p65 subunit of NFκB. The methylated K sites in vitro. Interestingly, the NFκB signaling activated by include K37, K218, K221, K310, K314, and K315 that are TNF can also induce proina fl mmatory chemokines, such as modified by different histone-modifying enzymes. Among CCL20, CXCL13, and CXCL8, that are specic fi ligands for 111,112 the histone methyl transferases, SET9, SETD6, and NSD1 are the chemokine receptor CXCR2 in ovarian cancer cells. capable of activating NFκB by methylating K218 and K221 It is a positive-feedback loop that high expression of proin- of p65, which provides a potential mechanism for how NSD1 flammatory genes in the tumor microenvironment can be might contribute to tumor formation, as constitutive activa- increased through activation of canonical and noncanonical tion of NFκB is a hallmark of many cancers. Methylation NFκB pathways to accelerate the development of tumors of NFκB can profoundly affect the functions of NFκB by and also promote the expression of proina fl mmatory proteins altering its stability, transactivation potency, and affinity to through binding of specific dimers of activated NF κB to DNA, and thus affect the strength and duration of inducible promoters of proina fl mmatory genes. For example, IL1 can gene expression. Meanwhile, the differential methylation induce the phosphorylation of MKK4, which is indispensable submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 Dovepress Xia et al Dovepress in the processing of NFκB p100 to the p52-active form and to enhancement of the ability of NFκB binding to DNA 10,113 translocation of p52 from the cytoplasm to the nucleus. and activation of NFκB, which can induce mesenchymal Besides the proinflammatory function, NF κB has a direct anti- trans-differentiation and radioresistance. Similarly, the inflammatory effect. NF κB can inhibit the formation of inflam - activation of mTORC1 induced by LMP1 is a key regulator masomes through inhibition of inflammasome-dependent of the NFκB pathway in NPC cells. With knockdown of caspase 1 activation, but the mechanism is not entirely the MTORC1 gene, activation of NFκB induced by LMP1 and clear and is probably related to NFκB-induced expres- the transcription of Glut1 are markedly inhibited, negatively sion of antiapoptotic proteins, such as PAI2 and Bcl-xL. affecting the aerobic glycolysis in nasopharyngeal carcinoma cell HONE1. Therefore, the activation of NFκB pathway Protumorigenic roles of NFκB plays an important role in regulating the energy metabolism The potential role of NFκB in oncogenesis was confirmed of nasopharyngeal carcinoma cells. in the discovery of the retroviral oncogene v-Rel, the homologue of the gene encoding cRel, one of the NFκB Antitumorigenic roles of NFκB subunits. The genes encoding NFκB subunits or IκB The role of NFκB in cancer is not always positive. Researchers proteins are mutated in a variety of malignancies. Mutations have found that blockade of NFκB via overexpression of and gene fusions of IKKA, which leads to the activation of IκBα promoted oncogenic Ras-induced invasive epidermal IKKα, were detected in breast cancer, where the activation growth, resembling squamous-cell carcinoma. The overex- of IKKα can maintain the self-renewal of breast cancer pression of IκBα induced by ablation of IKKβ can enhance progenitors and has been shown to be responsible for the the stability of IκB by inhibition of the phosphorylated tumor-promoting effects of progesterone in breast cancer. IκBα protein, resulting in inactivation of canonical NFκB. However, the number of tumors with persistently activated In addition, the high expression of IKKβ that activates clas- nuclear NFκB is much larger than the subfraction of malig- sical and nonclassical NFκB can suppress the progression nancies with confirmed mutations in NF κB or IκB-encoding of hepatocellular carcinoma by preventing DEN-induced 105 126 genes. In breast cancer, colon cancer, and lymphatic can- cell death. Meanwhile, ablation of IKKβ can enhance the cer, the persistent activation of the NFκB-signaling pathway activation of JNK family members, including JNK1, which leads to abnormal cell proliferation and differentiation, contributes to hepatocellular carcinoma development. 102,117,118 enhanced metastasis, and treatment resistance. In Functional cross-talk between Nrf2 and NFκB/RelA pro- colitis-associated colon cancer, positive effects of NFκB tects the liver from necrosis, inflammation, and fibrosis, and have been shown by conditional silencing of IKKβ, which thus prevents development of hepatocellular adenoma. persistently activates NFκB in intestinal epithelial cells. Transcription factors Nrf2 and NFκB regulate the cellular Recent studies have found that the Epstein–Barr virus antioxidant defense system, which is important in cell (EBV) in several T- and NK-cell neoplasms can persistently survival. Recently, researchers found that LCN2 is a activate NFκB via the viral protein LMP1, resembling the upstream regulatory gene of the NFκB–Snail pathway and proteins in the TNF-receptor superfamily that induce NFκB can inhibit the phosphorylation of p65 (p-p65) and the nuclear 120,121 activation through interaction with TRAF and TRADD, accumulation of p-p65 and Snail to inhibit activation of the and contribute to development of EBV-positive T- and NK- NFκB pathway, thereby inhibiting colorectal cancer cell cell neoplasms. epithelial–mesenchymal transition and metastasis induced by Mutations in upstream NFκB effectors in tumor cells the NFκB–Snail pathway. However, a number of studies will also result in the activation of the NFκB pathway, and have suggested that the NFκB pathway may upregulate the then the persistent activation of NFκB can specic fi ally target expression of LCN2 to promote the development of many 131,132 the promoters of oncogenes to form a positive-feedback cancers. Therefore, the NFκB pathway is diversified 133,134 loop. For instance, BRCA1 silencing in breast cancer cell in different tumor cells, and the complex anticancer lines induces phosphorylation of the Ser536 site of p65 and mechanism of the NFκB pathway is still not clear. Further processing of p100/p52, causing constitutive activation of the study is warranted. canonical NFκB pathway (p65/p50) and noncanonical NFκB pathway (p100/p52) and promoting the nuclear translocation Prospects of NFκB inhibitors and accumulationof p52/RelB, which can enhance prolifera- It is unquestionable that NFκB inhibition as a means of cancer tion of MCF1 cells. In glioma stem cells, MLK4 binds treatment has to be prioritized. Hundreds of NFκB inhibitors to and phosphorylates the NFκB regulator IKKα, leading have been developed. These inhibitors are mainly designed submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 Dovepress Dovepress NFκB pathway in cancer to target one of four key points in the NFκB pathway: IKKs, extensive studies to ensure and optimize the expected thera- NFκB-subunit dimers, proteasome 26S in the case of protea- peutic benefit in the future. some inhibitors, and the Ub-ligase complex in the case of ubiquitination blockers. These four elements are essential Conclusion to activation of the NFκB pathway. Moreover, natural prod- As a molecular hub linking inflammation and cancer, ucts, antioxidants, nonsteroidal anti-ina fl mmatory drugs, and NFκB has been established as a crucial contributor in the glucocorticoids are capable of interfering with the NFκB- development of malignant tumors. Although inhibition of signaling cascade. As the phosphorylation step of IκBα is a NFκB activity is incapable of fully suppressing the growth common reaction for the NFκB signaling induced by diverse of cancer, expression of NFκB components and activated stimuli, IKK inhibitors are considered an interesting approach NFκB signaling still reflect a potentially serious risk of for NFκB modulation. After phosphorylation of IκBα, the malignancies. Despite great progress in targeting NFκB polyubiquitination and proteasomal degradation of the IκBα signaling for cancer therapy, NFκB inhibitors have not been protein will result in NFκB release for translocation to the put into clinical application. Exploration of more effective nucleus. Therefore, ubiquitination blockers and proteasome and specific NF κB-targeted anticancer strategies is needed. inhibitors could also be considered as interesting modulators With the development of technology, the inhibition of NFκB of the NFκB cascade. by a variety of inhibitors may pave the way for future per- Many NFκB inhibitors have demonstrated appreciable sonalized treatment strategies. anticancer activity in preclinical approaches. For example, BAY11-7082 can specifically abolish the binding of p65 to Acknowledgments targeted DNA and downregulate the expression of TNFα. This work was supported in part by grants from the National As an IKKβ inhibitor, EF24 can block the NFκB-signaling Natural Science Foundation of China (81472595, 81402006) pathway by inhibiting IKKβ phosphorylation, leading to and the Research Project of the Health and Family Planning cell-cycle arrest at the G /M phase and apoptosis. The Commission of Hunan Province (B20180400, B20180582). proteasome inhibitor MG132 inhibits tumor growth through LZX and SMT are first co-authors for this study. 141,142 downregulation of the NFκB-signaling pathway. In addition, T901 is a novel selective NFκB inhibitor function- Author contributions ing through binding to the NFκB complex in the cytosol, LZX and SMT contributed to drafting and editing of the thus blocking its nuclear translocation and target-gene manuscript. DLC and QJL designed, revised, and finalized expression. Although many NFκB inhibitors have been the manuscript. HRW and LDO participated in drafting and developed to exert antitumor effects in a variety of experi- editing of the manuscript. YJZ participated in revision and mental cancer models, ranging from lymphoma to solid coordination. JGL, YTT, and LL contributed to the literature 144–146 tumors, no such drug has been clinically approved. search. MS and HW participated in conception and coordina- Because the mechanism of the antitumor effect of NFκB tion. All authors contributed toward data analysis and drafting inhibitors is not totally understood, many NFκB inhibitors and revising the paper, and agree to be accountable for all are not effective as a single antitumor agent. The alterations aspects of the work. of cellular signaling induced by NFκB inhibitors are gener- ally involved in the establishment, evolution, and spread of Disclosure malignant tumors. Therefore, considering the positive role The authors report no conflicts of interest in this work. of NFκB in the vast majority of cancer pathogenesis, NFκB inhibitors that are able to modulate more than one therapeutic References target related to this disease are currently considered the most 1. Yu AF, Ky B. Roadmap for biomarkers of cancer therapy cardiotoxicity. Heart. 2016;102(6):425–430. promising alternatives to single anticancer drugs. Due to 2. Katada C, Yokoyama T, Yano T, et al. Alcohol consumption and multiple the wide range of possibilities to regulate the NFκB-signaling dysplastic lesions increase risk of squamous cell carcinoma in the esopha- pathway, targeting different key points along the cascade gus, head, and neck. Gastroenterology. 2016;151(5):860.e7–869.e7. 3. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global offers a major opportunity. The challenge of NFκB inhibitors cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108. being applied in clinical intervention as novel anticancer-drug 4. Cao W, Kayama H, Chen ML, et al. The xenobiotic transporter Mdr1 enforces T cell homeostasis in the presence of intestinal bile acids. candidates lies in whether or not these NFκB inhibitors have Immunity. 2017;47(6):1182.e10–1196.e10. better pharmacotherapeutic and safety profiles. Therefore, 5. Chen H, Huang Q, Dong J, Lan Q. [Cancer initiating cell theory: popular- this approach still requires some improvements and more ity and controversies]. Ai Zheng. 2006;25(6):779–784. Chinese. submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 Dovepress Xia et al Dovepress 6. Adjei AA, Hidalgo M. Intracellular signal transduction pathway proteins 30. Marienfeld RB, Palkowitsch L, Ghosh S. Dimerization of the IκB as targets for cancer therapy. J Clin Oncol. 2005;23(23):5386–5403. kinase-binding domain of NEMO is required for tumor necrosis 7. Zhang W, Yin G, Dai J, et al. Chemoprevention by quercetin of oral factor alpha-induced NF-κB activity. Mol Cell Biol. 2006;26(24): squamous cell carcinoma by suppression of the NF-κB signaling pathway 9209–9219. in DMBA-treated hamsters. Anticancer Res. 2017;37(8):4041–4049. 31. DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M. 8. Sun Y, Fan X, Zhang Q, Shi X, Xu G, Zou C. Cancer-associated fibro - A cytokine-responsive IκB kinase that activates the transcription factor blasts secrete FGF-1 to promote ovarian proliferation, migration, and NF-κB. Nature. 1997;388(6642):548–554. invasion through the activation of FGF-1/FGFR4 signaling. Tumour 32. Annemann M, Plaza-Sirvent C, Schuster M, et al. Atypical IκB pro- Biol. 2017;39(7):1010428317712592. teins in immune cell differentiation and function. Immunol Lett. 2016; 9. Baud V, Karin M. Is NF-κB a good target for cancer therapy? Hopes 171:26–35. and pitfalls. Nat Rev Drug Discov. 2009;8(1):33–40. 33. Sivanandan S, Naganathan AN. A disorder-induced domino-like desta- 10. Kim JS, Kim EJ, Kim HS, Kurie JM, Ahn YH. MKK4 activates non- bilization mechanism governs the folding and functional dynamics of canonical NFκB signaling by promoting NFκB2-p100 processing. the repeat protein IκBα. PLoS Comput Biol. 2013;9(12):e1003403. Biochem Biophys Res Commun. 2017;491(2):337–342. 34. Roth S, Rottach A, Lotz-Havla AS, et al. Rad50-CARD9 interactions 11. Xing Y, Wang X, Jameson SC, Hogquist KA. Late stages of T cell link cytosolic DNA sensing to IL-1β production. Nat Immunol. 2014; maturation in the thymus involve NF-κB and tonic type I interferon 15(6):538–545. signaling. Nat Immunol. 2016;17(5):565–573. 35. Schneider AT, Gautheron J, Feoktistova M, et al. RIPK1 suppresses a 12. Li Y, Zhou QL, Sun W, et al. Non-canonical NF-κB signalling and TRAF2-dependent pathway to liver cancer. Cancer Cell. 2017;31(1): ETS1/2 cooperatively drive C250T mutant TERT promoter activation. 94–109. Nat Cell Biol. 2015;17(10):1327–1338. 36. Kelly PN, Romero DL, Yang Y, et al. Selective interleukin-1 receptor- 13. Wang H, Zhu Y, Xu X, et al. Ctenopharyngodon idella NF-κB subunit associated kinase 4 inhibitors for the treatment of autoimmune disorders p65 modulates the transcription of IκBα in CIK cells. Fish Shellfish and lymphoid malignancy. J Exp Med. 2015;212(13):2189–2201. Immunol. 2016;54:564–572. 37. Abdul-Sater AA, Edilova MI, Clouthier DL, Mbanwi A, Kremmer E, 14. Shen LQ, Xu X, Liang HP, Li SM. [Screening of polypeptides interact- Watts TH. The signaling adaptor TRAF1 negatively regulates Toll- ing with Rel homology domain of NF-κB p50 subunit]. Xi Bao Yu Fen like receptor signaling and this underlies its role in rheumatic disease. Zi Mian Yi Xue Za Zhi. 2007;23(9):804–806. Chinese. Nat Immunol. 2017;18(1):26–35. 15. Merchant M, Morkotinis V, Hale A, White M, Moran C. Crocodylian 38. Kinpara S, Ito S, Takahata T, et al. Involvement of double-stranded nuclear factor κB. Comp Biochem Physiol B Biochem Mol Biol. 2017; RNA-dependent protein kinase and antisense viral RNA in the con- 213:28–34. stitutive NFκB activation in adult T-cell leukemia/lymphoma cells. 16. Keogh CE, Scholz CC, Rodriguez J, Selfridge AC, von Kriegsheim A, Leukemia. 2015;29(6):1425–1429. Cummins EP. Carbon dioxide-dependent regulation of NF-κB family 39. He H, Chang R, Zhang T, Yang C, Kong Z. ATM mediates DAB2IP- members RelB and p100 gives molecular insight into CO -dependent dec fi ient bladder cancer cell resistance to ionizing radiation through the immune regulation. J Biol Chem. 2017;292(27):11561–11571. p38MAPK and NF-κB signaling pathway. Mol Med Rep. 2017;16(2): 17. Tong L, Yuan Y, Wu S. Therapeutic microRNAs targeting the NF-κB 1216–1222. signaling circuits of cancers. Adv Drug Deliv Rev. 2015;81:1–15. 40. Pak C, Miyamoto S. A new alpha in line between KRAS and NF-κB 18. Isoda K, Roth S, Nusslein-Volhard C. The functional domains of the activation? Cancer Discov. 2013;3(6):613–615. Drosophila morphogen dorsal: evidence from the analysis of mutants. 41. Baeuerle PA, Baltimore D. Activation of DNA-binding activity in an Genes Dev. 1992;6(4):619–630. apparently cytoplasmic precursor of the NF-κB transcription factor. 19. Annunziata CM, Davis RE, Demchenko Y, et al. Frequent engagement of Cell. 1988;53(2):211–217. the classical and alternative NF-κB pathways by diverse genetic abnor- 42. Brady G, Haas DA, Farrell PJ, Pichlmair A, Bowie AG. Molluscum malities in multiple myeloma. Cancer Cell. 2007;12(2):115–130. contagiosum virus protein MC005 inhibits NF-κB activation by tar- 20. Sies H, Berndt C, Jones DP. Oxidative stress. Annu Rev Biochem. 2017; geting NEMO-regulated IκB kinase activation. J Virol. 2017;91(15): 86:715–748. e00545. 21. Espinosa L, Bigas A, Mulero MC. Novel functions of chromatin- 43. Briggs LC, Chan AW, Davis CA, et al. IKKγ-mimetic peptides block bound IκBα in oncogenic transformation. Br J Cancer. 2014;111(9): the resistance to apoptosis associated with Kaposi’s sarcoma-associated 1688–1692. herpesvirus infection. J Virol. 2017;91(23):e01170. 22. Paul M, Kemparaju K, Girish KS. Inhibition of constitutive NF-κB 44. Wu YH, Huang YF, Chang TH, Chou CY. Activation of TWIST1 by activity induces platelet apoptosis via ER stress. Biochem Biophys Res COL11A1 promotes chemoresistance and inhibits apoptosis in ovarian Commun. 2017;493(4):1471–1477. cancer cells by modulating NF-κB-mediated IKKβ expression. Int J 23. Rao P, Hayden MS, Long M, et al. IκBβ acts to inhibit and activate gene Cancer. 2017;141(11):2305–2317. expression during the inflammatory response. Nature. 2010;466(7310): 45. Petersheim D, Massaad MJ, Lee S, et al. Mechanisms of genotype- 1115–1119. phenotype correlation in autosomal dominant anhidrotic ectodermal 24. Whiteside ST, Epinat JC, Rice NR, Israel A. IκB epsilon, a novel mem- dysplasia with immune deficiency. J Allergy Clin Immunol. Epub 2017 ber of the IκB family, controls RelA and cRel NF-κB activity. EMBO J. Jun 17. 1997;16(6):1413–1426. 46. Pujari R, Hunte R, Thomas R, et al. Human T-cell leukemia virus 25. Thompson JE, Phillips RJ, Erdjument-Bromage H, Tempst P, Ghosh S. type 1 (HTLV-1) tax requires CADM1/TSLC1 for inactivation of the IκB-β regulates the persistent response in a biphasic activation of NF-κB inhibitor A20 and constitutive NF-κB signaling. PLoS Pathog. NF-κB. Cell. 1995;80(4):573–582. 2015;11(3):e1004721. 26. Durand JK, Baldwin AS. Targeting IKK and NF-κB for therapy. 47. Li CC, Dai RM, Longo DL. Inactivation of NF-κB inhibitor IκBα: Adv Protein Chem Struct Biol. 2017;107:77–115. ubiquitin-dependent proteolysis and its degradation product. Biochem 27. Tao Z, Fusco A, Huang DB, et al. p100/IκBδ sequesters and inhibits Biophys Res Commun. 1995;215(1):292–301. NF-κB through κB some formation. Proc Natl Acad Sci U S A. 2014; 48. Geng Z, Wei L, Zhang C, Yan X. Astragalus polysaccharide a com- 111(45):15946–15951. ponent of traditional Chinese medicine inhibits muscle cell atrophy 28. Karin M. Nuclear factor-κB in cancer development and progression. (cachexia) in an in vivo and in vitro rat model of chronic renal failure Nature. 2006;441(7092):431–436. by activating the ubiquitin-proteasome pathway. Exp Ther Med. 2017; 29. Xiao G, Rabson AB, Young W, Qing G, Qu Z. Alternative pathways of 14(1):91–96. NF-κB activation: a double-edged sword in health and disease. Cytokine 49. Chen ZJ. Ubiquitination in signaling to and activation of IKK. Growth Factor Rev. 2006;17(4):281–293. Immunol Rev. 2012;246(1):95–106. submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 Dovepress Dovepress NFκB pathway in cancer 50. Sunami Y, Ringelhan M, Kokai E, et al. Canonical NF-κB signaling 74. Elliott PR, Leske D, Hrdinka M, et al. SPATA2 links CYLD to LUBAC, in hepatocytes acts as a tumor-suppressor in hepatitis B virus surface activates CYLD, and controls LUBAC signaling. Mol Cell. 2016;63(6): antigen-driven hepatocellular carcinoma by controlling the unfolded 990–1005. protein response. Hepatology. 2016;63(5):1592–1607. 75. Fiil BK, Gyrd-Hansen M. Met1-linked ubiquitination in immune 51. Dejardin E. The alternative NF-κB pathway from biochemistry to signalling. FEBS J. 2014;281(19):4337–4350. biology: pitfalls and promises for future drug development. Biochem 76. Zhong X, Lee HN, Surh YJ. RvD1 inhibits TNFα-induced c-Myc Pharmacol. 2006;72(9):1161–1179. expression in normal intestinal epithelial cells and destabilizes hyper- 52. Hayden MS, Ghosh S. Shared principles in NF-κB signaling. Cell. 2008; expressed c-Myc in colon cancer cells. Biochem Biophys Res Commun. 132(3):344–362. 2018;496(2):316–323. 53. Cildir G, Low KC, Tergaonkar V. Noncanonical NF-κB signaling in 77. Ghosh S, Dass JF. Study of pathway cross-talk interactions with NF-κB health and disease. Trends Mol Med. 2016;22(5):414–429. leading to its activation via ubiquitination or phosphorylation: a brief 54. Sun SC. Non-canonical NF-κB signaling pathway. Cell Res. 2011;21(1): review. Gene. 2016;584(1):97–109. 71–85. 78. Zeng KW, Liao LX, Lv HN, et al. Natural small molecule FMHM 55. Sun SC. The noncanonical NF-κB pathway. Immunol Rev. 2012;246(1): inhibits lipopolysaccharide-induced inflammatory response by promot - 125–140. ing TRAF6 degradation via K48-linked polyubiquitination. Sci Rep. 56. Almaden JV, Liu YC, Yang E, et al. B-cell survival and development 2015;5:14715. controlled by the coordination of NF-κB family members RelB and 79. Wang Y, Zhao W, Gao Q, et al. pVHL mediates K63-linked ubiq- cRel. Blood. 2016;127(10):1276–1286. uitination of IKKβ leading to IKKβ inactivation. Cancer Lett. 2016; 57. Willmann KL, Sacco R, Martins R, et al. Expanding the interactome of 383(1):1–8. the noncanonical NF-κB signaling pathway. J Proteome Res. 2016;15(9): 80. Jiang X, Chen ZJ. The role of ubiquitylation in immune defence and 2900–2909. pathogen evasion. Nat Rev Immunol. 2011;12(1):35–48. 58. Al-Sadi R, Guo S, Ye D, Rawat M, Ma TY. TNF-α modulation of 81. Lu X, Yarbrough WG. Negative regulation of RelA phosphorylation: intestinal tight junction permeability is mediated by NIK/IKK-α axis emerging players and their roles in cancer. Cytokine Growth Factor activation of the canonical NF-κB Pathway. Am J Pathol. 2016;186(5): Rev. 2015;26(1):7–13. 1151–1165. 82. Afonina IS, Zhong Z, Karin M, Beyaert R. Limiting inflammation: 59. Ho SC, Wu SM, Feng PH, et al. Noncanonical NF-κB mediates the the negative regulation of NF-κB and the NLRP3 inflammasome. Nat suppressive effect of neutrophil elastase on IL-8/CXCL8 by inducing Immunol. 2017;18(8):861–869. NKRF in human airway smooth muscle. Sci Rep. 2017;7:44930. 83. Ren L, Li Z, Dai C, et al. Chrysophanol inhibits proliferation and induces 60. Hu H, Brittain GC, Chang JH, et al. OTUD7B controls non-canonical apoptosis through NF-κB/cyclin D1 and NF-κB/Bcl-2 signaling cascade NF-κB activation through deubiquitination of TRAF3. Nature. 2013; in breast cancer cell lines. Mol Med Rep. 2018;17(3):4376–4382. 494(7437):371–374. 84. Wang Y, Qin X, Zhu X, Chen W, Zhang J, Chen W. Oral cancer-derived 61. Sundaram GM, Bramhachari PV. Molecular interplay of pro-ina fl mmatory exosomal NAP1 enhances cytotoxicity of natural killer cells via the transcription factors and non-coding RNAs in esophageal squamous IRF-3 pathway. Oral Oncol. 2018;76:34–41. cell carcinoma. Tumour Biol. 2017;39(6):1010428317705760. 85. Zhong H, Voll RE, Ghosh S. Phosphorylation of NF-κB p65 by PKA 62. Gilmore TD. Introduction to NF-κB: players pathways perspectives. stimulates transcriptional activity by promoting a novel bivalent interac- Oncogene. 2006;25(51):6680–6684. tion with the coactivator CBP/p300. Mol Cell. 1998;1(5):661–671. 63. Moles A, Butterworth JA, Sanchez A, et al. A RelA(p65) Thr505 86. Liu Y, Mayo MW, Nagji AS, et al. Phosphorylation of RelA/p65 pro- phospho-site mutation reveals an important mechanism regulating motes DNMT-1 recruitment to chromatin and represses transcription NF-κB-dependent liver regeneration and cancer. Oncogene. 2016;35(35): of the tumor metastasis suppressor gene BRMS1. Oncogene. 2012; 4623–4632. 31(9):1143–1154. 64. Delcourt V, Franck J, Leblanc E, et al. Combined mass spectrometry 87. Gunster RA, Matthews SA, Holden DW, Thurston TL. SseK1 and imaging and top-down microproteomics reveals evidence of a hidden SseK3 type III secretion system effectors inhibit NF-κB signaling proteome in ovarian cancer. EBioMedicine. 2017;21:55–64. and necroptotic cell death in Salmonella-infected macrophages. Infect 65. Richard SA, Jiang Y, Xiang LH, et al. Post-translational modifications Immun. 2017;85(3):e00010. of high mobility group box 1 and cancer. Am J Transl Res. 2017;9(12): 88. Wang H, Cebotaru L, Lee HW, et al. CFTR controls the activity of 5181–5196. NF-κB by enhancing the degradation of TRADD. Cell Physiol Biochem. 66. Hirata Y, Takahashi M, Morishita T, Noguchi T, Matsuzawa A. Post- 2016;40(5):1063–1078. translational modifications of the TAK1-TAB complex. Int J Mol Sci. 89. Lv F, Huang Y, Lv W, et al. MicroRNA-146a Ameliorates inflamma - 2017;18(1):E205. tion via TRAF6/NF-κB pathway in intervertebral disc cells. Med Sci 67. Viatour P, Merville MP, Bours V, Chariot A. Phosphorylation of NF-κB Monit. 2017;23:659–664. and IκB proteins: implications in cancer and inflammation. Trends 90. Sun J, Yu X, Wang C, et al. RIP-1/c-FLIPL induce hepatic cancer cell Biochem Sci. 2005;30(1):43–52. apoptosis through regulating tumor necrosis factor-related apoptosis- 68. O’Shea JM, Perkins ND. Regulation of the RelA (p65) transactivation inducing ligand (TRAIL). Med Sci Monit. 2017;23:1190–1199. domain. Biochem Soc Trans. 2008;36(Pt 4):603–608. 91. Chirieleison SM, Kertesy SB, Abbott DW. Synthetic biology reveals 69. Perkins ND. Post-translational modic fi ations regulating the activity and the uniqueness of the RIP kinase domain. J Immunol. 2016;196(10): function of the nuclear factor κB pathway. Oncogene. 2006;25(51): 4291–4297. 6717–6730. 92. Richardson JS, Aminudin N, Malek SN. Chalepin: a compound from 70. Won M, Byun HS, Park KA, Hur GM. Post-translational control of Ruta angustifolia L. pers exhibits cell cycle arrest at S phase suppresses NF-κB signaling by ubiquitination. Arch Pharm Res. 2016;39(8): nuclear factor-Κ B (NF-κB) pathway signal transducer and activation 1075–1084. of transcription 3 (STAT3) phosphorylation and extrinsic apoptotic 71. Wang YC, Peterson SE, Loring JF. Protein post-translational modifi - pathway in non-small cell lung cancer carcinoma (A549). Pharmacogn cations and regulation of pluripotency in human stem cells. Cell Res. Mag. 2017;13(51):489–498. 2014;24(2):143–160. 93. Lu T, Stark GR. NF-κB: regulation by methylation. Cancer Res. 2015; 72. Pickart CM. Back to the future with ubiquitin. Cell. 2004;116(2): 75(18):3692–3695. 181–190. 94. Levy D, Kuo AJ, Chang Y, et al. Lysine methylation of the NF-κB 73. Rieser E, Cordier SM, Walczak H. Linear ubiquitination: a newly dis- subunit RelA by SETD6 couples activity of the histone methyltrans- covered regulator of cell signalling. Trends Biochem Sci. 2013;38(2): ferase GLP at chromatin to tonic repression of NF-κB signaling. Nat 94–102. Immunol. 2011;12(1):29–36. submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 Dovepress Xia et al Dovepress 95. Ea CK, Baltimore D. Regulation of NF-κB activity through lysine 117. Forlani G, Abdallah R, Accolla RS, Tosi G. The major histocompat- monomethylation of p65. Proc Natl Acad Sci U S A. 2009;106(45): ibility complex class II transactivator CIITA inhibits the persistent 18972–18977. activation of NF-κB by the human T cell lymphotropic virus type 1 96. Lu T, Yang M, Huang DB, et al. Role of lysine methylation of NF-κB in Tax-1 Oncoprotein. J Virol. 2016;90(7):3708–3721. differential gene regulation. Proc Natl Acad Sci U S A. 2013;110(33): 118. Walther W, Kobelt D, Bauer L, Aumann J, Stein U. Chemosensitiza- 13510–13515. tion by diverging modulation by short-term and long-term TNF-α 97. Song W, Mazzieri R, Yang T, Gobe GC. Translational significance action on ABCB1 expression and NF-κB signaling in colon cancer. for tumor metastasis of tumor-associated macrophages and epithelial- Int J Oncol. 2015;47(6):2276–2285. mesenchymal transition. Front Immunol. 2017;8:1106. 119. Greten FR, Eckmann L, Greten TF, et al. IKKβ links inflammation 98. Zhong L, Chen XF, Wang T, et al. Soluble TREM2 induces ina fl mmatory and tumorigenesis in a mouse model of colitis-associated cancer. Cell. responses and enhances microglial survival. J Exp Med. 2017;214(3): 2004;118(3):285–296. 597–607. 120. Kieser A. Pursuing different “TRADDes”: TRADD signaling induced 99. Vlantis K, Wullaert A, Polykratis A, et al. NEMO prevents RIP kinase 1- by TNF-receptor 1 and the Epstein-Barr virus oncoprotein LMP1. Biol mediated epithelial cell death and chronic intestinal inflammation Chem. 2008;389(10):1261–1271. by NF-κB-dependent and -independent functions. Immunity. 2016; 121. Luftig M, Yasui T, Soni V, et al. Epstein-Barr virus latent infec- 44(3):553–567. tion membrane protein 1 TRAF-binding site induces NIK/IKK 100. Tosello V, Bordin F, Yu J, et al. Calcineurin and GSK-3 inhibition α-dependent noncanonical NF-κB activation. Proc Natl Acad Sci sensitizes T-cell acute lymphoblastic leukemia cells to apoptosis U S A. 2004;101(1):141–146. through X-linked inhibitor of apoptosis protein degradation. Leukemia. 122. Takada H, Imadome KI, Shibayama H, et al. EBV induces persistent 2016;30(4):812–822. NF-κB activation and contributes to survival of EBV-positive neo- 101. Kwon HJ, Choi GE, Ryu S, et al. Stepwise phosphorylation of p65 plastic T- or NK-cells. PLoS One. 2017;12(3):e0174136. promotes NF-κB activation and NK cell responses during target cell 123. Kim SH, Ezhilarasan R, Phillips E, et al. Serine/threonine kinase recognition. Nat Commun. 2016;7:11686. MLK4 determines mesenchymal identity in glioma stem cells in an 102. Sau A, Lau R, Cabrita MA, et al. Persistent activation of NF-κB in NF-κB-dependent manner. Cancer Cell. 2016;29(2):201–213. BRCA1-dec fi ient mammary progenitors drives aberrant proliferation 124. Zhang J, Jia L, Lin W, et al. Epstein-Barr virus-encoded latent mem- and accumulation of DNA damage. Cell Stem Cell. 2016;19(1):52–65. brane protein 1 upregulates glucose transporter 1 transcription via the 103. Salazar L, Kashiwada T, Krejci P, et al. Fibroblast growth factor mTORC1/NF-κB signaling pathways. J Virol. 2017;91(6):e02168. receptor 3 interacts with and activates TGFβ-activated kinase 1 125. Dajee M, Lazarov M, Zhang JY, et al. NF-κB blockade and oncogenic tyrosine phosphorylation and NFκB signaling in multiple myeloma Ras trigger invasive human epidermal neoplasia. Nature. 2003; and bladder cancer. PLoS One. 2014;9(1):e86470. 421(6923):639–643. 104. Liu F, Bardhan K, Yang D, et al. NF-κB directly regulates Fas tran- 126. Luedde T, Beraza N, Kotsikoris V, et al. Deletion of NEMO/IKKγ scription to modulate Fas-mediated apoptosis and tumor suppression. in liver parenchymal cells causes steatohepatitis and hepatocellular J Biol Chem. 2012;287(30):25530–25540. carcinoma. Cancer Cell. 2007;11(2):119–132. 105. Ben-Neriah Y, Karin M. Inflammation meets cancer with NF- κB as 127. Sakurai T, He G, Matsuzawa A, et al. Hepatocyte necrosis induced by the matchmaker. Nat Immunol. 2011;12(8):715–723. oxidative stress and IL-1α release mediate carcinogen-induced com- 106. Grivennikov SI, Greten FR, Karin M. Immunity inflammation and pensatory proliferation and liver tumorigenesis. Cancer Cell. 2008; cancer. Cell. 2010;140(6):883–899. 14(2):156–165. 107. Smale ST. Hierarchies of NF-κB target-gene regulation. Nat Immunol. 128. Kohler UA, Böhm F, Rolfs F, et al. NF-κB/RelA and Nrf2 cooperate 2011;12(8):689–694. to maintain hepatocyte integrity and to prevent development of hepa- 108. Kiechl S, Wittmann J, Giaccari A, et al. Blockade of receptor activa- tocellular adenoma. J Hepatol. 2016;64(1):94–102. tor of nuclear factor-κB (RANKL) signaling improves hepatic insulin 129. Schreck R, Rieber P, Baeuerle PA. Reactive oxygen intermediates resistance and prevents development of diabetes mellitus. Nat Med. as apparently widely used messengers in the activation of the NF-κB 2013;19(3):358–363. transcription factor and HIV-1. EMBO J. 1991;10(8):2247–2258. 109. Kondegowda NG, Fenutria R, Pollack IR, et al. Osteoprotegerin and 130. Feng M, Feng J, Chen W, et al. Lipocalin 2 suppresses metastasis of denosumab stimulate human beta cell proliferation through inhibi- colorectal cancer by attenuating NF-κB-dependent activation of snail tion of the receptor activator of NF-κB ligand pathway. Cell Metab. and epithelial mesenchymal transition. Mol Cancer. 2016;15(1):77. 2015;22(1):77–85. 131. Kaur S, Sharma N, Krishn SR, et al. MUC4-mediated regulation of 110. Zanotto-Filho A, Gonçalves RM, Klafke K, et al. Inflammatory land - acute phase protein lipocalin 2 through HER2/AKT/NF-κB signaling scape of human brain tumors reveals an NFκB dependent cytokine in pancreatic cancer. Clin Cancer Res. 2014;20(3):688–700. pathway associated with mesenchymal glioblastoma. Cancer Lett. 132. Mahadevan NR, Rodvold J, Almanza G, Perez AF, Wheeler MC, 2017;390:176–187. Zanetti M. ER stress drives lipocalin 2 upregulation in prostate cancer 111. Son DS, Kabir SM, Dong Y, Lee E, Adunyah SE. Characteristics of cells in an NF-κB-dependent manner. BMC Cancer. 2011;11:229. chemokine signatures elicited by EGF and TNF in ovarian cancer 133. Shi Z, Hu Z, Chen D, et al. MicroRNA-200a mediates nasopharyn- cells. J Inflamm (Lond) . 2013;10(1):25. geal carcinoma cell proliferation through the activation of nuclear 112. Olson TS, Ley K. Chemokines and chemokine receptors in leukocyte factor-κB. Mol Med Rep. 2016;13(2):1732–1738. trafficking. Am J Physiol Regul Integr Comp Physiol. 2002;283(1): 134. Wang Y, Ren F, Wang Y, et al. CHIP/Stub1 functions as a tumor sup- R7–R28. pressor and represses NF-κB-mediated signaling in colorectal cancer. 113. Banerjee S, McGee DW. ROCK activity affects IL-1-induced signaling Carcinogenesis. 2014;35(5):983–991. possibly through MKK4 and p38 MAPK in Caco-2 cells. In Vitro Cell 135. Erstad DJ, Cusack JC Jr. Targeting the NF-κB pathway in cancer Dev Biol Anim. 2016;52(8):878–884. therapy. Surg Oncol Clin N Am. 2013;22(4):705–746. 114. Greten FR, Arkan MC, Bollrath J, et al. NF-κB is a negative regulator 136. Gupta SC, Sundaram C, Reuter S, Aggarwal BB. Inhibiting NF-κB of IL-1β secretion as revealed by genetic and pharmacological inhibi- activation by small molecules as a therapeutic strategy. Biochim tion of IKKβ. Cell. 2007;130(5):918–931. Biophys Acta. 2010;1799(10–12):775–787. 115. Gilmore TD. The Re1/NF-κB/IκB signal transduction pathway and 137. Castro AC, Dang LC, Soucy F, et al. Novel IKK inhibitors: cancer. Cancer Treat Res. 2003;115:241–265. β-carbolines. Bioorg Med Chem Lett. 2003;13(14):2419–2422. 116. Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature. 138. Gilmore TD, Herscovitch M. Inhibitors of NF-κB signaling:785 and 2009;458(7239):719–724. counting. Oncogene. 2006;25(51):6887–6899. submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 Dovepress Dovepress NFκB pathway in cancer 139. Wu CY, Ke Y, Zeng YF, Zhang YW, Yu HJ. Anticancer activity of 146. Qian C, Chen X, Qi Y, et al. Sporamin induces apoptosis and inhibits Astragalus polysaccharide in human non-small cell lung cancer cells. NF-κB activation in human pancreatic cancer cells. Tumour Biol. Cancer Cell Int. 2017;17:115. 2017;39(7):1010428317706917. 140. Jin R, Chen Q, Yao S, et al. Synthesis and anti-tumor activity of EF24 147. Oida K, Matsuda A, Jung K, et al. Nuclear factor-kB plays a critical analogues as IKKβ inhibitors. Eur J Med Chem. 2017;144:218–228. role in both intrinsic and acquired resistance against endocrine therapy 141. Zhang Y, Yang B, Zhao J, Li X, Zhang L, Zhai Z. Proteasome inhibitor in human breast cancer cells. Sci Rep. 2014;4:4057. carbobenzoxy-l-leucyl-l-leucyl-l-leucinal (MG132) enhances thera- 148. Chen F, Castranova V, Shi X. New insights into the role of nuclear peutic effect of paclitaxel on breast cancer by inhibiting nuclear factor factor-κB in cell growth regulation. Am J Pathol. 2001;159(2): (NF)-κB signaling. Med Sci Monit. 2018;24:294–304. 387–397. 142. Sun F, Zhang Y, Xu L, et al. Proteasome inhibitor MG132 enhances 149. Barbosa ML, da Conceicao RA, Fraga AG, et al. NF-κB signaling cisplatin-induced apoptosis in osteosarcoma cells and inhibits tumor pathway inhibitors as anticancer drug candidates. Anticancer Agents growth. Oncol Res. Epub 2017 Nov 30. Med Chem. 2017;17(4):483–490. 143. Vaisitti T, Gaudino F, Ouk S, et al. Targeting metabolism and survival 150. Capece D, Verzella D, Tessitore A, Alesse E, Capalbo C, Zazzeroni F. in chronic lymphocytic leukemia and Richter syndrome cells by a Cancer secretome and inflammation: the bright and the dark sides of novel NF-κB inhibitor. Haematologica. 2017;102(11):1878–1889. NF-κB. Semin Cell Dev Biol. Epub 2017 Aug 2. 144. Vu KT, Zhang F, Hulleman JD. Conditional genetically encoded small molecule-regulated inhibition of NFκB signaling in RPE cells. Invest Ophthalmol Vis Sci. 2017;58(10):4126–4137. 145. Pollock N, Taylor G, Jobe F, Guzman E. Modulation of the transcrip- tion factor NF-κB in antigen-presenting cells by bovine respiratory syncytial virus small hydrophobic protein. J Gen Virol. 2017;98(7): 1587–1599. OncoTargets and Therapy Dovepress Publish your work in this journal OncoTargets and Therapy is an international, peer-reviewed, open patient perspectives such as quality of life, adherence and satisfaction. access journal focusing on the pathological basis of all cancers, potential The manuscript management system is completely online and includes targets for therapy and treatment protocols employed to improve the a very quick and fair peer-review system, which is all easy to use. Visit management of cancer patients. The journal also focuses on the impact http://www.dovepress.com/testimonials.php to read real quotes from of management programs and new therapeutic agents and protocols on published authors. Submit your manuscript here: http://www.dovepress.com/oncotargets-and-therapy-journal submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 Dovepress http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png OncoTargets and therapy Pubmed Central

Role of the NFκB-signaling pathway in cancer

Download PDF
11 pages

Loading next page...
 
/lp/pubmed-central/role-of-the-nf-b-signaling-pathway-in-cancer-gPIYEqkg7r

References (152)

Publisher
Pubmed Central
Copyright
© 2018 Xia et al. This work is published and licensed by Dove Medical Press Limited
ISSN
1178-6930
eISSN
1178-6930
DOI
10.2147/OTT.S161109
Publisher site
See Article on Publisher Site

Abstract

Journal name: OncoTargets and Therapy Article Designation: Review Year: 2018 Volume: 11 Running head verso: Xia et al OncoTargets and Therapy Dovepress Running head recto: NFκB pathway in cancer open access to scientific and medical research DOI: 161109 Open Access Full Text Article Review 1, Longzheng Xia * Abstract: Cancer is a group of cells that malignantly grow and proliferate uncontrollably. 1, At present, treatment modes for cancer mainly comprise surgery, chemotherapy, radiotherapy, Shiming Tan * molecularly targeted therapy, gene therapy, and immunotherapy. However, the curative effects Yujuan Zhou of these treatments have been limited thus far by specific characteristics of tumors. Abnormal Jingguan Lin 1 activation of signaling pathways is involved in tumor pathogenesis and plays critical roles in Heran w ang growth, progression, and relapse of cancers. Targeted therapies against effectors in oncogenic Linda Oyang signaling have improved the outcomes of cancer patients. NFκB is an important signaling Yutong Tian pathway involved in pathogenesis and treatment of cancers. Excessive activation of the NFκB- Lu Liu signaling pathway has been documented in various tumor tissues, and studies on this signaling Min Su pathway for targeted cancer therapy have become a hot topic. In this review, we update current Hui w ang understanding of the NFκB-signaling pathway in cancer. 1,2 Deliang Cao Keywords: nuclear factor kappa-B, p65, signaling pathway, cancer, inflammation Qianjin Liao Hunan Key Laboratory of Introduction Translational Radiation Oncology, Malignant tumors have become one of the most deadly diseases and a prominent Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School public health problem threatening human lives around the world. In recent years, of Medicine, Changsha, Hunan, China; 2 with social and economic development, as well as aging of the population, the inci- Department of Medical Microbiology, immunology, and Cell Biology, dence and mortality of cancer are increasing. The overall incidence of common Simmons Cancer institute, Southern malignant tumors will rise from 14 million in 2012 to a predicted 19 million in 2025 illinois University School of Medicine, 3,4 Springfield, iL, USA and 24 million in 2035, according to the World Health Organization. Cancer occurs due to oncogene activation, tumor-suppressor gene inactivation, loss of control of the *These authors contributed equally to this work 5 cell cycle, genomic instability, telomerase loss, and resistance of apoptosis. However, the specific pathogenesis of cancer varies with types of cancers. The cell-signaling pathway is the process by which cell responds to stimuli of extracellular signaling molecules that bind to receptors located on the cell membrane or in the cytoplasm of cells. This binding to receptors transfers signals to the nucleus and induces corresponding gene expression, thus producing biological effects and 6 7,8 cellular responses. In tumorigenesis, signaling pathways are less controlled. Abnormal regulation and cross-talk of cell-signal-transduction pathways play a Correspondence: Qianjin Liao; key role in cancer, and obstruction of or anomalies in signaling pathways may Deliang Cao Hunan Key Laboratory of Translational lead to excessive cell proliferation, apoptotic resistance, angiogenesis, invasion, Radiation Oncology, Hunan Cancer and metastasis, leading to development and progression of cancer. NFκB is an Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central important signaling pathway that is involved extensively in cancer development and South University, 283 Tongzipo Road, progression. Through controlling the expression of target genes, such as TNFA, IL6, Changsha, Hunan 410013, China Tel +86 731 8865 1681 BCLXL, BCL2, BCLXS, XIAP, and VEGF, NFκB mediates tumor-cell proliferation, Fax +86 731 8865 1999 survival, and angiogenesis. This review focuses on this NFκB-signaling pathway email [email protected]; [email protected] in tumors. submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 2063–2073 Dovepress © 2018 Xia et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/OTT.S161109 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Xia et al Dovepress Overview of NFκB-signaling present in cells in the form of their precursors. In these members, RelB can form dimers only with p50 or p52, but pathways others can form either homologous or heterologous dimers. Proteins and structure of NFκB family However, the most common NFκB dimer is the heterodimer NFκB is an important transcription-factor family of five of p65–p50. These homologous and/or heterologous dim- subunits: Rel (cRel), p65 (RelA, NFκB3), RelB, p105/p50 ers can bind to a specific sequence (ie, NF κB sites) of the 10–12 (NFκB1), and p100/p52 (NFκB2). Among these, p65, target gene to regulate gene transcription. Therefore, NFκB cRel, and RelB contain an N-terminal Rel-homologous regulates the activity of cells through the slight difference in domain (RHD; about 300 amino acids) and a C-terminal binding of these NFκB dimers to targeted sequences. 13,14 transactivation domain (TAD; Figure 1), while p50 and 15,16 p52 have only an RHD, but not a TAD. The C-terminal of p100 and p105 contains ankyrin repeats that function as iκBs and iKKs a p52 and p50 inhibitor. The RHD is responsible for DNA IκBs and IKKs are upstream regulators of the NFκB- binding and dimerization between different or identical signaling pathway. In cells that are not stimulated, NFκB family members, including the nuclear localization sequence dimers are present in an inactive state by binding to three and IκB-binding region, leading to homomeric or hetero- inhibitory factors (IκBα, IκBβ, and IκBε) of the NFκB in the meric binding of the subunits. The TAD is associated only cytoplasm, which blocks the nuclear localization sequence 18 20,21 with transcriptional activation. Therefore, the p50–p52 and prevents the NFκB from transition into the nucleus. homologous dimer does not activate gene transcription, but In addition, there are also two precursor IκBs: p105/IκBγ acts as an inhibitory molecule. Both p50 and p52 are usually and p100/IκBδ. IκBα specifically inhibits the p50/RelA 71)αSURLQIODPPDWRU\F\WRNLQHV β5&'%5%$))5 OLSLGSRO\VDFFKDULGHVJURZWK 5$1. IDFWRUVDQGDQWLJHQV &HOOUHFHSWRU &HOOUHFHSWRU ,..α ,..β 5HO% ,κ%α ,..γ β7 U&3 S 1,. 8E ,..α 8E 8E S S ,κ%α ,κ%α 5HO% 5HO% S S S 8E 5HO% 1XFOHXV '1$ ELQGLQJDQGJHQHWUDQVFULSWLRQ Figure 1 Structure of NFκB members. Notes: The NFκB family consists of three proteins with a transactivation domain (RelA [p65], cRel, and RelB) and two proteins lacking a transactivation domain (p105/p50 and p100/p52). Similarly, only p105/p50 and p100/p52 have ankyrin repeats that function as p52 and p50 inhibitors. However, all these proteins share an Rel-homology domain, associated with DNA binding, dimerization, nuclear localization and iκB binding, and nuclear localization signal exposure, which is vital to the translocation of the dimer into the nucleus. Abbreviation: NiK, NFκB-inducing kinase. submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 Dovepress /7 Dovepress NFκB pathway in cancer heterodimer, IκBβ targets the RelA/cRel heterodimer, and phosphorylation speed of the same IKK for IκBα and IκBβ IκBε inhibits the RelA and cRel dimers. Although different are different. IKKβ has stronger affinity for I κBα than IκBβ. external stimuli cause differential activation of NFκB through Also, the IκB-kinase complex can phosphorylate the NFκB- different IκBs, almost all known NFκB agonists can rap- bound IκB protein and contribute to proteasomal degradation 26 32 idly and transiently activate NFκB by degradation of IκBs. of the IκB protein faster. The IκB proteins p105/IκBγ and p100/IκBδ play a dual role, ie, precursors of the NFκB proteins p50 and p52 and inhibi- Activation of NFκB-signaling pathway tors of NFκB signaling. Different external stimuli have In a resting status of cells, complexes formed from NFκB differential effects on the different subunits of IκBs, leading and IκB (NFκB–IκBα or NFκB–IκBε) shuttle between the to differential activation of the NFκB pathway. cytoplasm and nucleus in a dynamic equilibrium. When cells The IKK (IκB kinase) complex consists of the catalytic are stimulated by extracellular signals, such as TNFα, IL1, subunits IKKα and IKKβ and the regulatory subunit NFκB lipopolysaccharide, viral double-stranded RNA, and ionizing essential modifier (NEMO; also called IKK γ). The IKKs radiation, NFκB is activated and enters the nucleus to bind to 28 34–39 are upstream regulators of IκBs. Both IKKα and IKKβ target genes. Upon activation, NFκB-signaling pathways subunits have about 52% of the sequence identity, but play are classified as canonical or noncanonical (Figure 2). The a key but divergent role in regulation of global NFκB- common regulatory step in both pathways is activation of the signaling activity. NEMO contains several domains that IKK complex. The IKK complex is phosphorylated, and in are crucial for its function as a regulatory subunit of the turn induces phosphorylation of IκB proteins IκBα or IκBβ, canonical IKK complex. The N-terminal coiled-coil domain leading to ubiquitination and degradation by proteasomes. of NEMO interacts with IKKα and IKKβ. Different IKKs Similarly, p100 and p105 are phosphorylated and cleaved demonstrate differential strength and speed for different into maturated p52 and p50 upon IKK activation. Therefore, substrates. IKKα is mainly the specific upstream kinase of NFκB dimers are released from their inhibitors and free to IκBβ and can strongly phosphorylate the Ser23 of IκBβ, but translocate into the nucleus to regulate expression of their not the Ser19. This inequivalent phosphorylation of Ser23 target genes. and Ser19 in IκBβ leads to degradation of IκBβ. IKKβ can The canonical NFκB-transcription factor is an inactive specifically phosphorylate the Ser sites of I κBα and IκBβ, dimer composed of a p50 and RelA/p65 subunit, which and the intensity is 20 times that of IKKα. In addition, the largely resides in the cytoplasm as part of a latent complex 5HOKRPRORJRXV $QN\ULQ GRPDLQ SS 5+' 1/6 SS 5+' 1/6 ,QWHUGRPDLQOLQNHU 1/6SRO\SHSWLGH 7 UDQVDFWLYDWLRQGRPDLQ 5HO$  S 5+' 1/6 ' 5HO% 5+' 1/6 ' F5HO 5+' 1/6 ' Figure 2 Activation of NFκB cascade by the classical/canonical signaling pathway (right) and alternative/noncanonical signaling pathway (left). Abbreviations: NLS, nuclear localization sequence; RHD, Rel-homologous domain; TAD, transactivation domain. submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 Dovepress 7$ 7$ 7$ Xia et al Dovepress 41,42 with IκBα under basal conditions. The formation of p65 Ubiquitination, a PTM of addition of ubiquitin (Ub) (RelA)–p50 or p65–cRel heterodimers is a key to activation. moieties to a protein, is the primary mechanism of protein Stimulation by proinflammatory cytokines, such as TNF α, turnover in the cell, and is recognized as the “traditional” IL1β, TLR ligands, and T-cell-receptor activators, results function of Ub tagging. Ub moieties on NFκB-signaling in activation of the IKKβ complex, and then IκBα is phos- proteins can serve as a docking platform for other proteins 44,45 72 phorylated at Ser32 and Ser36 by the IKK complex, with specific Ub-binding domains. First, the Ub moiety is 46–49 polyubiquitinated at K63, and degraded by proteasomes. activated by the E1 Ub-activating enzyme. Following acti- Degradation of IκBα consequently releases the canonical vation, one of several E2 Ub-conjugating enzymes transfers NFκB dimer p50-RelA/p65 to translocate into the nucleus Ub from E1 to several E3 enzymes (Ub ligases), to which and activate gene transcription. the substrate protein is specifically bound. The Ub moiety Although the canonical NFκB pathway has been more includes seven lysine (K) residues (K6, K11, K27, K29, K33, extensively studied, it is not to be ignored that the nonca- K48, and K63) and a methionine at the N-terminus (M1), nonical pathway (or alternative NFκB pathway) is vital in which can link another Ub to form a polyUb chain. some aspects. This alternative pathway is activated by TNF- Ub signaling controls activation of NFκB and innate receptor (TNFR) family members, such as LTβR, BAFFR, immunoresponses downstream of pattern-recognition recep- 52–56 RANK, and CD40. Once the receptor is activated, TRAF tors, such as Toll-like receptors, nucleotide-oligomerization proteins are able to mediate the activity of NFκB-inducing domain-like receptors, and cytokine receptors, eg, TNFR1, in 57,58 74–76 kinase and activate an IKKα homodimer at the same time, normal intestinal epithelial cells and colon cancer cells. ultimately leading to heterodimerization of the p100 precur- K48-linked polyubiquitination is a key step in releasing sor with RelB and processing into the active p52 subunit. NFκB from IκBs in the canonical pathway and processing of This processing of p100 induces the generation of the non- p100/102 into p52/50 in the noncanonical pathway to activate canonical transcription factor, a p52-RelB dimer, which then the NFκB pathway in inflammatory diseases, autoimmune 70,77,78 binds to κB DNA-binding sites and controls expression of diseases, and cancers. The Skp1–Cullin–F-box (SCF)– targeted genes. Therefore, activation of these two pathways βTrCP complex catalyzes the K48-linked polyubiquitination is achieved by phosphorylation of IκB proteins, which relieve of IκBα at two N-terminal lysine residues (K21 and K22), the inhibition of IκB proteins to NFκB dimers. inducing 26S proteasome-dependent degradation of IκBα and nuclear translocation of canonical NFκB. In addition, the Posttranslational modifications of phosphorylation of IκBα induced by NFκB-inducing kinase NFκB proteins could cause the phosphorylation of p100 on the C-terminal NFκB has hundreds of validated transcriptional targets, region (Ser866 and Ser870) and polyubiquitination of p100 and thus NFκB-signaling activity is under stringent spatial by the SCF–βTrCP–E3 ligase complex to regulate the activity and temporal control at the levels of nuclear transloca- of the noncanonical NFκB. The IKKβ subunit is also tion and posttranslational modic fi ations (PTMs) of signaling polyubiquitinated by a K63-linked chain in human cervical 61,62 79 components. There is a wide range of PTMs of NFκB HeLa cells. Importantly, activation of IKK is essential to subunits, and PTMs provide essential mechanisms differ- productive signaling and NFκB-mediated transcription, and entially to regulate NFκB-signaling activity in response to its activation depends on the binding of Met1-Ub by the IKK the various stimuli that activate this pathway in many cancer subunit NEMO. 64,65 cells. Although these modifications have a critical role Phosphorylation is critical for NFκB activity, including in the normal and pathological functions of NFκB in vivo, binding to and transcription of genes that contain a con- the physiological significance of PTMs remains unclear in sensus sequence. Phosphorylation of key NFκB-signaling cancer cells. PTMs not only can contribute to the control molecules often positively mediates signal transduction by of nuclear translocation but also have an important inu fl ence inducing protein conformational changes in breast cancer 82,83 in functions of NFκB subunits, including protein degrada- cell lines. Activation of NFκB signaling is involved in a 67–69 tion, DNA binding, and transcriptional activity. PTMs of series of phosphorylation events of upstream NFκB regula- NFκB include phosphorylation, ubiquitination, acetylation, tors and NFκB family members. In fact, the activity of NFκB and methylation. Herein, we focus on the ubiquitination, is controlled to a great extent by phosphorylation of RelA or phosphorylation, and methylation of the functional subunits upstream regulators in esophageal squamous-cell carcinoma, 81,84 of NFκB. gastric cancer, and oral cancer. The main subunit RelA of submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 Dovepress Dovepress NFκB pathway in cancer NFκB is targeted for phosphorylation at many phosphoac- of K37 and K218/221 on NFκB is able to constitute “bar ceptor sites within both the RHD (Ser205, Ser276, Ser281, codes” that guide differential activation of NFκB, binding Ser311, and Thr254) and TAD (Ser468, Ser529, Ser535, to specific promoters. Ser536, Thr435, and Thr505). For example, the phospho- rylation of Ser536 induced in the cytoplasm can increase Roles of NFκB in cancer NFκB transcriptional activity, while phosphorylation of At present, the role of the NFκB-signaling pathway in cell Ser529 increases DNA binding and oligomerization in biogenic activities is the hot spot of cancer research. NFκB laryngeal cancer cells. The phosphorylation of Ser536 signaling is involved in cellular immunity, ina fl mmation, and results in nuclear accumulation of RelA through disruption stress, as well as regulation of cell differentiation, prolifera- 97–101 of the cytoplasmic/nuclear shuttling of NFκB–IκBα com- tion, and apoptosis. The NFκB pathway is often altered plexes. In addition, phosphorylation of Ser276 can promote in both solid and hematopoietic malignancies, promoting 52,102,103 RelA interaction with the transcriptional coactivator CBP/ tumor-cell proliferation and survival. However, recent p300. Meanwhile, p-Ser276 RelA facilitates recruitment of evidence indicates that NFκB plays a tumor-suppressive role DNMT1/DNA (cytosine 5)–methyltransferase 1 to chromatin in certain cancers through transcriptional activation of the and subsequent BRMS1-promoter methylation and tran- Fas ligand. scriptional repression in human NSCLC cells. In addition, Pro- and anti-inflammatory effects of phosphorylation of IκBs is a key step of their proteasomal degradation and the release of NFκB for nuclear translocation NFκB and activation of gene transcription. Cytokines in the tumor The pathogenic role of inflammation in cancer has drawn microenvironment, such as TNFα, could bind to the cell- intensive research and highlighted the context-dependent surface TNF receptor, causing TNF-receptor multimerization modulation of inflammation-associated cancer by the tran - 87,88 105 and interacting with TRADD in the cytoplasm. TRADD scription factor NFκB. Through control of inflammatory 89 90 recruits TRAF and kinase RIP. Then, the stimulated responses, NFκB has influence in tumor development and signals are transmitted to IKK by RIP, which can make the progression by excessive innate immunity activation and Ser32 and Ser36 residues in α-subunits of IκB and Ser19 abnormal cell growth. Ina fl mmation-associated cancer can 91,92 and Ser23 residues in β-subunits of IκB phosphorylated. secrete various cytokines and chemokines through NFκB Then, IκB protein is dissociated from the p50-p65-IκB trimer binding to the promoters of genes, such as IL1B, TNF, and and subsequently degraded by proteasomes, activating the IL6. At the same time, activation of NFκB can be regulated 77 108,109 NFκB pathway. by the TNFα-receptor family, including RANKL. In recent years, accumulated evidence has suggested that It is well known that ina fl mmatory gene signatures are histone-modifying enzymes not only modify histone proteins altered in various tumor-cell lines and specimens of differ- but also play a role in the modic fi ation of nonhistone proteins, ent histological and molecular subtypes. Researchers have such as NFκB. NFκB can be methylated reversibly on lysine found that the inflammatory genes, such as IL1, IL6, IL8, or arginine residues by histone-modifying enzymes, including and CCL2, are also actively expressed in glioma-cell lines, lysine and arginine methyl transferases and demethylases. playing differential and cooperative roles in promoting prolif- The methylations of both lysine and arginine occur mainly eration, invasion, angiogenesis, and macrophage polarization 94,95 110 on the p65 subunit of NFκB. The methylated K sites in vitro. Interestingly, the NFκB signaling activated by include K37, K218, K221, K310, K314, and K315 that are TNF can also induce proina fl mmatory chemokines, such as modified by different histone-modifying enzymes. Among CCL20, CXCL13, and CXCL8, that are specic fi ligands for 111,112 the histone methyl transferases, SET9, SETD6, and NSD1 are the chemokine receptor CXCR2 in ovarian cancer cells. capable of activating NFκB by methylating K218 and K221 It is a positive-feedback loop that high expression of proin- of p65, which provides a potential mechanism for how NSD1 flammatory genes in the tumor microenvironment can be might contribute to tumor formation, as constitutive activa- increased through activation of canonical and noncanonical tion of NFκB is a hallmark of many cancers. Methylation NFκB pathways to accelerate the development of tumors of NFκB can profoundly affect the functions of NFκB by and also promote the expression of proina fl mmatory proteins altering its stability, transactivation potency, and affinity to through binding of specific dimers of activated NF κB to DNA, and thus affect the strength and duration of inducible promoters of proina fl mmatory genes. For example, IL1 can gene expression. Meanwhile, the differential methylation induce the phosphorylation of MKK4, which is indispensable submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 Dovepress Xia et al Dovepress in the processing of NFκB p100 to the p52-active form and to enhancement of the ability of NFκB binding to DNA 10,113 translocation of p52 from the cytoplasm to the nucleus. and activation of NFκB, which can induce mesenchymal Besides the proinflammatory function, NF κB has a direct anti- trans-differentiation and radioresistance. Similarly, the inflammatory effect. NF κB can inhibit the formation of inflam - activation of mTORC1 induced by LMP1 is a key regulator masomes through inhibition of inflammasome-dependent of the NFκB pathway in NPC cells. With knockdown of caspase 1 activation, but the mechanism is not entirely the MTORC1 gene, activation of NFκB induced by LMP1 and clear and is probably related to NFκB-induced expres- the transcription of Glut1 are markedly inhibited, negatively sion of antiapoptotic proteins, such as PAI2 and Bcl-xL. affecting the aerobic glycolysis in nasopharyngeal carcinoma cell HONE1. Therefore, the activation of NFκB pathway Protumorigenic roles of NFκB plays an important role in regulating the energy metabolism The potential role of NFκB in oncogenesis was confirmed of nasopharyngeal carcinoma cells. in the discovery of the retroviral oncogene v-Rel, the homologue of the gene encoding cRel, one of the NFκB Antitumorigenic roles of NFκB subunits. The genes encoding NFκB subunits or IκB The role of NFκB in cancer is not always positive. Researchers proteins are mutated in a variety of malignancies. Mutations have found that blockade of NFκB via overexpression of and gene fusions of IKKA, which leads to the activation of IκBα promoted oncogenic Ras-induced invasive epidermal IKKα, were detected in breast cancer, where the activation growth, resembling squamous-cell carcinoma. The overex- of IKKα can maintain the self-renewal of breast cancer pression of IκBα induced by ablation of IKKβ can enhance progenitors and has been shown to be responsible for the the stability of IκB by inhibition of the phosphorylated tumor-promoting effects of progesterone in breast cancer. IκBα protein, resulting in inactivation of canonical NFκB. However, the number of tumors with persistently activated In addition, the high expression of IKKβ that activates clas- nuclear NFκB is much larger than the subfraction of malig- sical and nonclassical NFκB can suppress the progression nancies with confirmed mutations in NF κB or IκB-encoding of hepatocellular carcinoma by preventing DEN-induced 105 126 genes. In breast cancer, colon cancer, and lymphatic can- cell death. Meanwhile, ablation of IKKβ can enhance the cer, the persistent activation of the NFκB-signaling pathway activation of JNK family members, including JNK1, which leads to abnormal cell proliferation and differentiation, contributes to hepatocellular carcinoma development. 102,117,118 enhanced metastasis, and treatment resistance. In Functional cross-talk between Nrf2 and NFκB/RelA pro- colitis-associated colon cancer, positive effects of NFκB tects the liver from necrosis, inflammation, and fibrosis, and have been shown by conditional silencing of IKKβ, which thus prevents development of hepatocellular adenoma. persistently activates NFκB in intestinal epithelial cells. Transcription factors Nrf2 and NFκB regulate the cellular Recent studies have found that the Epstein–Barr virus antioxidant defense system, which is important in cell (EBV) in several T- and NK-cell neoplasms can persistently survival. Recently, researchers found that LCN2 is a activate NFκB via the viral protein LMP1, resembling the upstream regulatory gene of the NFκB–Snail pathway and proteins in the TNF-receptor superfamily that induce NFκB can inhibit the phosphorylation of p65 (p-p65) and the nuclear 120,121 activation through interaction with TRAF and TRADD, accumulation of p-p65 and Snail to inhibit activation of the and contribute to development of EBV-positive T- and NK- NFκB pathway, thereby inhibiting colorectal cancer cell cell neoplasms. epithelial–mesenchymal transition and metastasis induced by Mutations in upstream NFκB effectors in tumor cells the NFκB–Snail pathway. However, a number of studies will also result in the activation of the NFκB pathway, and have suggested that the NFκB pathway may upregulate the then the persistent activation of NFκB can specic fi ally target expression of LCN2 to promote the development of many 131,132 the promoters of oncogenes to form a positive-feedback cancers. Therefore, the NFκB pathway is diversified 133,134 loop. For instance, BRCA1 silencing in breast cancer cell in different tumor cells, and the complex anticancer lines induces phosphorylation of the Ser536 site of p65 and mechanism of the NFκB pathway is still not clear. Further processing of p100/p52, causing constitutive activation of the study is warranted. canonical NFκB pathway (p65/p50) and noncanonical NFκB pathway (p100/p52) and promoting the nuclear translocation Prospects of NFκB inhibitors and accumulationof p52/RelB, which can enhance prolifera- It is unquestionable that NFκB inhibition as a means of cancer tion of MCF1 cells. In glioma stem cells, MLK4 binds treatment has to be prioritized. Hundreds of NFκB inhibitors to and phosphorylates the NFκB regulator IKKα, leading have been developed. These inhibitors are mainly designed submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 Dovepress Dovepress NFκB pathway in cancer to target one of four key points in the NFκB pathway: IKKs, extensive studies to ensure and optimize the expected thera- NFκB-subunit dimers, proteasome 26S in the case of protea- peutic benefit in the future. some inhibitors, and the Ub-ligase complex in the case of ubiquitination blockers. These four elements are essential Conclusion to activation of the NFκB pathway. Moreover, natural prod- As a molecular hub linking inflammation and cancer, ucts, antioxidants, nonsteroidal anti-ina fl mmatory drugs, and NFκB has been established as a crucial contributor in the glucocorticoids are capable of interfering with the NFκB- development of malignant tumors. Although inhibition of signaling cascade. As the phosphorylation step of IκBα is a NFκB activity is incapable of fully suppressing the growth common reaction for the NFκB signaling induced by diverse of cancer, expression of NFκB components and activated stimuli, IKK inhibitors are considered an interesting approach NFκB signaling still reflect a potentially serious risk of for NFκB modulation. After phosphorylation of IκBα, the malignancies. Despite great progress in targeting NFκB polyubiquitination and proteasomal degradation of the IκBα signaling for cancer therapy, NFκB inhibitors have not been protein will result in NFκB release for translocation to the put into clinical application. Exploration of more effective nucleus. Therefore, ubiquitination blockers and proteasome and specific NF κB-targeted anticancer strategies is needed. inhibitors could also be considered as interesting modulators With the development of technology, the inhibition of NFκB of the NFκB cascade. by a variety of inhibitors may pave the way for future per- Many NFκB inhibitors have demonstrated appreciable sonalized treatment strategies. anticancer activity in preclinical approaches. For example, BAY11-7082 can specifically abolish the binding of p65 to Acknowledgments targeted DNA and downregulate the expression of TNFα. This work was supported in part by grants from the National As an IKKβ inhibitor, EF24 can block the NFκB-signaling Natural Science Foundation of China (81472595, 81402006) pathway by inhibiting IKKβ phosphorylation, leading to and the Research Project of the Health and Family Planning cell-cycle arrest at the G /M phase and apoptosis. The Commission of Hunan Province (B20180400, B20180582). proteasome inhibitor MG132 inhibits tumor growth through LZX and SMT are first co-authors for this study. 141,142 downregulation of the NFκB-signaling pathway. In addition, T901 is a novel selective NFκB inhibitor function- Author contributions ing through binding to the NFκB complex in the cytosol, LZX and SMT contributed to drafting and editing of the thus blocking its nuclear translocation and target-gene manuscript. DLC and QJL designed, revised, and finalized expression. Although many NFκB inhibitors have been the manuscript. HRW and LDO participated in drafting and developed to exert antitumor effects in a variety of experi- editing of the manuscript. YJZ participated in revision and mental cancer models, ranging from lymphoma to solid coordination. JGL, YTT, and LL contributed to the literature 144–146 tumors, no such drug has been clinically approved. search. MS and HW participated in conception and coordina- Because the mechanism of the antitumor effect of NFκB tion. All authors contributed toward data analysis and drafting inhibitors is not totally understood, many NFκB inhibitors and revising the paper, and agree to be accountable for all are not effective as a single antitumor agent. The alterations aspects of the work. of cellular signaling induced by NFκB inhibitors are gener- ally involved in the establishment, evolution, and spread of Disclosure malignant tumors. Therefore, considering the positive role The authors report no conflicts of interest in this work. of NFκB in the vast majority of cancer pathogenesis, NFκB inhibitors that are able to modulate more than one therapeutic References target related to this disease are currently considered the most 1. Yu AF, Ky B. Roadmap for biomarkers of cancer therapy cardiotoxicity. Heart. 2016;102(6):425–430. promising alternatives to single anticancer drugs. Due to 2. Katada C, Yokoyama T, Yano T, et al. Alcohol consumption and multiple the wide range of possibilities to regulate the NFκB-signaling dysplastic lesions increase risk of squamous cell carcinoma in the esopha- pathway, targeting different key points along the cascade gus, head, and neck. Gastroenterology. 2016;151(5):860.e7–869.e7. 3. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global offers a major opportunity. The challenge of NFκB inhibitors cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108. being applied in clinical intervention as novel anticancer-drug 4. Cao W, Kayama H, Chen ML, et al. The xenobiotic transporter Mdr1 enforces T cell homeostasis in the presence of intestinal bile acids. candidates lies in whether or not these NFκB inhibitors have Immunity. 2017;47(6):1182.e10–1196.e10. better pharmacotherapeutic and safety profiles. Therefore, 5. Chen H, Huang Q, Dong J, Lan Q. [Cancer initiating cell theory: popular- this approach still requires some improvements and more ity and controversies]. Ai Zheng. 2006;25(6):779–784. Chinese. submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 Dovepress Xia et al Dovepress 6. Adjei AA, Hidalgo M. Intracellular signal transduction pathway proteins 30. Marienfeld RB, Palkowitsch L, Ghosh S. Dimerization of the IκB as targets for cancer therapy. J Clin Oncol. 2005;23(23):5386–5403. kinase-binding domain of NEMO is required for tumor necrosis 7. Zhang W, Yin G, Dai J, et al. Chemoprevention by quercetin of oral factor alpha-induced NF-κB activity. Mol Cell Biol. 2006;26(24): squamous cell carcinoma by suppression of the NF-κB signaling pathway 9209–9219. in DMBA-treated hamsters. Anticancer Res. 2017;37(8):4041–4049. 31. DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M. 8. Sun Y, Fan X, Zhang Q, Shi X, Xu G, Zou C. Cancer-associated fibro - A cytokine-responsive IκB kinase that activates the transcription factor blasts secrete FGF-1 to promote ovarian proliferation, migration, and NF-κB. Nature. 1997;388(6642):548–554. invasion through the activation of FGF-1/FGFR4 signaling. Tumour 32. Annemann M, Plaza-Sirvent C, Schuster M, et al. Atypical IκB pro- Biol. 2017;39(7):1010428317712592. teins in immune cell differentiation and function. Immunol Lett. 2016; 9. Baud V, Karin M. Is NF-κB a good target for cancer therapy? Hopes 171:26–35. and pitfalls. Nat Rev Drug Discov. 2009;8(1):33–40. 33. Sivanandan S, Naganathan AN. A disorder-induced domino-like desta- 10. Kim JS, Kim EJ, Kim HS, Kurie JM, Ahn YH. MKK4 activates non- bilization mechanism governs the folding and functional dynamics of canonical NFκB signaling by promoting NFκB2-p100 processing. the repeat protein IκBα. PLoS Comput Biol. 2013;9(12):e1003403. Biochem Biophys Res Commun. 2017;491(2):337–342. 34. Roth S, Rottach A, Lotz-Havla AS, et al. Rad50-CARD9 interactions 11. Xing Y, Wang X, Jameson SC, Hogquist KA. Late stages of T cell link cytosolic DNA sensing to IL-1β production. Nat Immunol. 2014; maturation in the thymus involve NF-κB and tonic type I interferon 15(6):538–545. signaling. Nat Immunol. 2016;17(5):565–573. 35. Schneider AT, Gautheron J, Feoktistova M, et al. RIPK1 suppresses a 12. Li Y, Zhou QL, Sun W, et al. Non-canonical NF-κB signalling and TRAF2-dependent pathway to liver cancer. Cancer Cell. 2017;31(1): ETS1/2 cooperatively drive C250T mutant TERT promoter activation. 94–109. Nat Cell Biol. 2015;17(10):1327–1338. 36. Kelly PN, Romero DL, Yang Y, et al. Selective interleukin-1 receptor- 13. Wang H, Zhu Y, Xu X, et al. Ctenopharyngodon idella NF-κB subunit associated kinase 4 inhibitors for the treatment of autoimmune disorders p65 modulates the transcription of IκBα in CIK cells. Fish Shellfish and lymphoid malignancy. J Exp Med. 2015;212(13):2189–2201. Immunol. 2016;54:564–572. 37. Abdul-Sater AA, Edilova MI, Clouthier DL, Mbanwi A, Kremmer E, 14. Shen LQ, Xu X, Liang HP, Li SM. [Screening of polypeptides interact- Watts TH. The signaling adaptor TRAF1 negatively regulates Toll- ing with Rel homology domain of NF-κB p50 subunit]. Xi Bao Yu Fen like receptor signaling and this underlies its role in rheumatic disease. Zi Mian Yi Xue Za Zhi. 2007;23(9):804–806. Chinese. Nat Immunol. 2017;18(1):26–35. 15. Merchant M, Morkotinis V, Hale A, White M, Moran C. Crocodylian 38. Kinpara S, Ito S, Takahata T, et al. Involvement of double-stranded nuclear factor κB. Comp Biochem Physiol B Biochem Mol Biol. 2017; RNA-dependent protein kinase and antisense viral RNA in the con- 213:28–34. stitutive NFκB activation in adult T-cell leukemia/lymphoma cells. 16. Keogh CE, Scholz CC, Rodriguez J, Selfridge AC, von Kriegsheim A, Leukemia. 2015;29(6):1425–1429. Cummins EP. Carbon dioxide-dependent regulation of NF-κB family 39. He H, Chang R, Zhang T, Yang C, Kong Z. ATM mediates DAB2IP- members RelB and p100 gives molecular insight into CO -dependent dec fi ient bladder cancer cell resistance to ionizing radiation through the immune regulation. J Biol Chem. 2017;292(27):11561–11571. p38MAPK and NF-κB signaling pathway. Mol Med Rep. 2017;16(2): 17. Tong L, Yuan Y, Wu S. Therapeutic microRNAs targeting the NF-κB 1216–1222. signaling circuits of cancers. Adv Drug Deliv Rev. 2015;81:1–15. 40. Pak C, Miyamoto S. A new alpha in line between KRAS and NF-κB 18. Isoda K, Roth S, Nusslein-Volhard C. The functional domains of the activation? Cancer Discov. 2013;3(6):613–615. Drosophila morphogen dorsal: evidence from the analysis of mutants. 41. Baeuerle PA, Baltimore D. Activation of DNA-binding activity in an Genes Dev. 1992;6(4):619–630. apparently cytoplasmic precursor of the NF-κB transcription factor. 19. Annunziata CM, Davis RE, Demchenko Y, et al. Frequent engagement of Cell. 1988;53(2):211–217. the classical and alternative NF-κB pathways by diverse genetic abnor- 42. Brady G, Haas DA, Farrell PJ, Pichlmair A, Bowie AG. Molluscum malities in multiple myeloma. Cancer Cell. 2007;12(2):115–130. contagiosum virus protein MC005 inhibits NF-κB activation by tar- 20. Sies H, Berndt C, Jones DP. Oxidative stress. Annu Rev Biochem. 2017; geting NEMO-regulated IκB kinase activation. J Virol. 2017;91(15): 86:715–748. e00545. 21. Espinosa L, Bigas A, Mulero MC. Novel functions of chromatin- 43. Briggs LC, Chan AW, Davis CA, et al. IKKγ-mimetic peptides block bound IκBα in oncogenic transformation. Br J Cancer. 2014;111(9): the resistance to apoptosis associated with Kaposi’s sarcoma-associated 1688–1692. herpesvirus infection. J Virol. 2017;91(23):e01170. 22. Paul M, Kemparaju K, Girish KS. Inhibition of constitutive NF-κB 44. Wu YH, Huang YF, Chang TH, Chou CY. Activation of TWIST1 by activity induces platelet apoptosis via ER stress. Biochem Biophys Res COL11A1 promotes chemoresistance and inhibits apoptosis in ovarian Commun. 2017;493(4):1471–1477. cancer cells by modulating NF-κB-mediated IKKβ expression. Int J 23. Rao P, Hayden MS, Long M, et al. IκBβ acts to inhibit and activate gene Cancer. 2017;141(11):2305–2317. expression during the inflammatory response. Nature. 2010;466(7310): 45. Petersheim D, Massaad MJ, Lee S, et al. Mechanisms of genotype- 1115–1119. phenotype correlation in autosomal dominant anhidrotic ectodermal 24. Whiteside ST, Epinat JC, Rice NR, Israel A. IκB epsilon, a novel mem- dysplasia with immune deficiency. J Allergy Clin Immunol. Epub 2017 ber of the IκB family, controls RelA and cRel NF-κB activity. EMBO J. Jun 17. 1997;16(6):1413–1426. 46. Pujari R, Hunte R, Thomas R, et al. Human T-cell leukemia virus 25. Thompson JE, Phillips RJ, Erdjument-Bromage H, Tempst P, Ghosh S. type 1 (HTLV-1) tax requires CADM1/TSLC1 for inactivation of the IκB-β regulates the persistent response in a biphasic activation of NF-κB inhibitor A20 and constitutive NF-κB signaling. PLoS Pathog. NF-κB. Cell. 1995;80(4):573–582. 2015;11(3):e1004721. 26. Durand JK, Baldwin AS. Targeting IKK and NF-κB for therapy. 47. Li CC, Dai RM, Longo DL. Inactivation of NF-κB inhibitor IκBα: Adv Protein Chem Struct Biol. 2017;107:77–115. ubiquitin-dependent proteolysis and its degradation product. Biochem 27. Tao Z, Fusco A, Huang DB, et al. p100/IκBδ sequesters and inhibits Biophys Res Commun. 1995;215(1):292–301. NF-κB through κB some formation. Proc Natl Acad Sci U S A. 2014; 48. Geng Z, Wei L, Zhang C, Yan X. Astragalus polysaccharide a com- 111(45):15946–15951. ponent of traditional Chinese medicine inhibits muscle cell atrophy 28. Karin M. Nuclear factor-κB in cancer development and progression. (cachexia) in an in vivo and in vitro rat model of chronic renal failure Nature. 2006;441(7092):431–436. by activating the ubiquitin-proteasome pathway. Exp Ther Med. 2017; 29. Xiao G, Rabson AB, Young W, Qing G, Qu Z. Alternative pathways of 14(1):91–96. NF-κB activation: a double-edged sword in health and disease. Cytokine 49. Chen ZJ. Ubiquitination in signaling to and activation of IKK. Growth Factor Rev. 2006;17(4):281–293. Immunol Rev. 2012;246(1):95–106. submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 Dovepress Dovepress NFκB pathway in cancer 50. Sunami Y, Ringelhan M, Kokai E, et al. Canonical NF-κB signaling 74. Elliott PR, Leske D, Hrdinka M, et al. SPATA2 links CYLD to LUBAC, in hepatocytes acts as a tumor-suppressor in hepatitis B virus surface activates CYLD, and controls LUBAC signaling. Mol Cell. 2016;63(6): antigen-driven hepatocellular carcinoma by controlling the unfolded 990–1005. protein response. Hepatology. 2016;63(5):1592–1607. 75. Fiil BK, Gyrd-Hansen M. Met1-linked ubiquitination in immune 51. Dejardin E. The alternative NF-κB pathway from biochemistry to signalling. FEBS J. 2014;281(19):4337–4350. biology: pitfalls and promises for future drug development. Biochem 76. Zhong X, Lee HN, Surh YJ. RvD1 inhibits TNFα-induced c-Myc Pharmacol. 2006;72(9):1161–1179. expression in normal intestinal epithelial cells and destabilizes hyper- 52. Hayden MS, Ghosh S. Shared principles in NF-κB signaling. Cell. 2008; expressed c-Myc in colon cancer cells. Biochem Biophys Res Commun. 132(3):344–362. 2018;496(2):316–323. 53. Cildir G, Low KC, Tergaonkar V. Noncanonical NF-κB signaling in 77. Ghosh S, Dass JF. Study of pathway cross-talk interactions with NF-κB health and disease. Trends Mol Med. 2016;22(5):414–429. leading to its activation via ubiquitination or phosphorylation: a brief 54. Sun SC. Non-canonical NF-κB signaling pathway. Cell Res. 2011;21(1): review. Gene. 2016;584(1):97–109. 71–85. 78. Zeng KW, Liao LX, Lv HN, et al. Natural small molecule FMHM 55. Sun SC. The noncanonical NF-κB pathway. Immunol Rev. 2012;246(1): inhibits lipopolysaccharide-induced inflammatory response by promot - 125–140. ing TRAF6 degradation via K48-linked polyubiquitination. Sci Rep. 56. Almaden JV, Liu YC, Yang E, et al. B-cell survival and development 2015;5:14715. controlled by the coordination of NF-κB family members RelB and 79. Wang Y, Zhao W, Gao Q, et al. pVHL mediates K63-linked ubiq- cRel. Blood. 2016;127(10):1276–1286. uitination of IKKβ leading to IKKβ inactivation. Cancer Lett. 2016; 57. Willmann KL, Sacco R, Martins R, et al. Expanding the interactome of 383(1):1–8. the noncanonical NF-κB signaling pathway. J Proteome Res. 2016;15(9): 80. Jiang X, Chen ZJ. The role of ubiquitylation in immune defence and 2900–2909. pathogen evasion. Nat Rev Immunol. 2011;12(1):35–48. 58. Al-Sadi R, Guo S, Ye D, Rawat M, Ma TY. TNF-α modulation of 81. Lu X, Yarbrough WG. Negative regulation of RelA phosphorylation: intestinal tight junction permeability is mediated by NIK/IKK-α axis emerging players and their roles in cancer. Cytokine Growth Factor activation of the canonical NF-κB Pathway. Am J Pathol. 2016;186(5): Rev. 2015;26(1):7–13. 1151–1165. 82. Afonina IS, Zhong Z, Karin M, Beyaert R. Limiting inflammation: 59. Ho SC, Wu SM, Feng PH, et al. Noncanonical NF-κB mediates the the negative regulation of NF-κB and the NLRP3 inflammasome. Nat suppressive effect of neutrophil elastase on IL-8/CXCL8 by inducing Immunol. 2017;18(8):861–869. NKRF in human airway smooth muscle. Sci Rep. 2017;7:44930. 83. Ren L, Li Z, Dai C, et al. Chrysophanol inhibits proliferation and induces 60. Hu H, Brittain GC, Chang JH, et al. OTUD7B controls non-canonical apoptosis through NF-κB/cyclin D1 and NF-κB/Bcl-2 signaling cascade NF-κB activation through deubiquitination of TRAF3. Nature. 2013; in breast cancer cell lines. Mol Med Rep. 2018;17(3):4376–4382. 494(7437):371–374. 84. Wang Y, Qin X, Zhu X, Chen W, Zhang J, Chen W. Oral cancer-derived 61. Sundaram GM, Bramhachari PV. Molecular interplay of pro-ina fl mmatory exosomal NAP1 enhances cytotoxicity of natural killer cells via the transcription factors and non-coding RNAs in esophageal squamous IRF-3 pathway. Oral Oncol. 2018;76:34–41. cell carcinoma. Tumour Biol. 2017;39(6):1010428317705760. 85. Zhong H, Voll RE, Ghosh S. Phosphorylation of NF-κB p65 by PKA 62. Gilmore TD. Introduction to NF-κB: players pathways perspectives. stimulates transcriptional activity by promoting a novel bivalent interac- Oncogene. 2006;25(51):6680–6684. tion with the coactivator CBP/p300. Mol Cell. 1998;1(5):661–671. 63. Moles A, Butterworth JA, Sanchez A, et al. A RelA(p65) Thr505 86. Liu Y, Mayo MW, Nagji AS, et al. Phosphorylation of RelA/p65 pro- phospho-site mutation reveals an important mechanism regulating motes DNMT-1 recruitment to chromatin and represses transcription NF-κB-dependent liver regeneration and cancer. Oncogene. 2016;35(35): of the tumor metastasis suppressor gene BRMS1. Oncogene. 2012; 4623–4632. 31(9):1143–1154. 64. Delcourt V, Franck J, Leblanc E, et al. Combined mass spectrometry 87. Gunster RA, Matthews SA, Holden DW, Thurston TL. SseK1 and imaging and top-down microproteomics reveals evidence of a hidden SseK3 type III secretion system effectors inhibit NF-κB signaling proteome in ovarian cancer. EBioMedicine. 2017;21:55–64. and necroptotic cell death in Salmonella-infected macrophages. Infect 65. Richard SA, Jiang Y, Xiang LH, et al. Post-translational modifications Immun. 2017;85(3):e00010. of high mobility group box 1 and cancer. Am J Transl Res. 2017;9(12): 88. Wang H, Cebotaru L, Lee HW, et al. CFTR controls the activity of 5181–5196. NF-κB by enhancing the degradation of TRADD. Cell Physiol Biochem. 66. Hirata Y, Takahashi M, Morishita T, Noguchi T, Matsuzawa A. Post- 2016;40(5):1063–1078. translational modifications of the TAK1-TAB complex. Int J Mol Sci. 89. Lv F, Huang Y, Lv W, et al. MicroRNA-146a Ameliorates inflamma - 2017;18(1):E205. tion via TRAF6/NF-κB pathway in intervertebral disc cells. Med Sci 67. Viatour P, Merville MP, Bours V, Chariot A. Phosphorylation of NF-κB Monit. 2017;23:659–664. and IκB proteins: implications in cancer and inflammation. Trends 90. Sun J, Yu X, Wang C, et al. RIP-1/c-FLIPL induce hepatic cancer cell Biochem Sci. 2005;30(1):43–52. apoptosis through regulating tumor necrosis factor-related apoptosis- 68. O’Shea JM, Perkins ND. Regulation of the RelA (p65) transactivation inducing ligand (TRAIL). Med Sci Monit. 2017;23:1190–1199. domain. Biochem Soc Trans. 2008;36(Pt 4):603–608. 91. Chirieleison SM, Kertesy SB, Abbott DW. Synthetic biology reveals 69. Perkins ND. Post-translational modic fi ations regulating the activity and the uniqueness of the RIP kinase domain. J Immunol. 2016;196(10): function of the nuclear factor κB pathway. Oncogene. 2006;25(51): 4291–4297. 6717–6730. 92. Richardson JS, Aminudin N, Malek SN. Chalepin: a compound from 70. Won M, Byun HS, Park KA, Hur GM. Post-translational control of Ruta angustifolia L. pers exhibits cell cycle arrest at S phase suppresses NF-κB signaling by ubiquitination. Arch Pharm Res. 2016;39(8): nuclear factor-Κ B (NF-κB) pathway signal transducer and activation 1075–1084. of transcription 3 (STAT3) phosphorylation and extrinsic apoptotic 71. Wang YC, Peterson SE, Loring JF. Protein post-translational modifi - pathway in non-small cell lung cancer carcinoma (A549). Pharmacogn cations and regulation of pluripotency in human stem cells. Cell Res. Mag. 2017;13(51):489–498. 2014;24(2):143–160. 93. Lu T, Stark GR. NF-κB: regulation by methylation. Cancer Res. 2015; 72. Pickart CM. Back to the future with ubiquitin. Cell. 2004;116(2): 75(18):3692–3695. 181–190. 94. Levy D, Kuo AJ, Chang Y, et al. Lysine methylation of the NF-κB 73. Rieser E, Cordier SM, Walczak H. Linear ubiquitination: a newly dis- subunit RelA by SETD6 couples activity of the histone methyltrans- covered regulator of cell signalling. Trends Biochem Sci. 2013;38(2): ferase GLP at chromatin to tonic repression of NF-κB signaling. Nat 94–102. Immunol. 2011;12(1):29–36. submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 Dovepress Xia et al Dovepress 95. Ea CK, Baltimore D. Regulation of NF-κB activity through lysine 117. Forlani G, Abdallah R, Accolla RS, Tosi G. The major histocompat- monomethylation of p65. Proc Natl Acad Sci U S A. 2009;106(45): ibility complex class II transactivator CIITA inhibits the persistent 18972–18977. activation of NF-κB by the human T cell lymphotropic virus type 1 96. Lu T, Yang M, Huang DB, et al. Role of lysine methylation of NF-κB in Tax-1 Oncoprotein. J Virol. 2016;90(7):3708–3721. differential gene regulation. Proc Natl Acad Sci U S A. 2013;110(33): 118. Walther W, Kobelt D, Bauer L, Aumann J, Stein U. Chemosensitiza- 13510–13515. tion by diverging modulation by short-term and long-term TNF-α 97. Song W, Mazzieri R, Yang T, Gobe GC. Translational significance action on ABCB1 expression and NF-κB signaling in colon cancer. for tumor metastasis of tumor-associated macrophages and epithelial- Int J Oncol. 2015;47(6):2276–2285. mesenchymal transition. Front Immunol. 2017;8:1106. 119. Greten FR, Eckmann L, Greten TF, et al. IKKβ links inflammation 98. Zhong L, Chen XF, Wang T, et al. Soluble TREM2 induces ina fl mmatory and tumorigenesis in a mouse model of colitis-associated cancer. Cell. responses and enhances microglial survival. J Exp Med. 2017;214(3): 2004;118(3):285–296. 597–607. 120. Kieser A. Pursuing different “TRADDes”: TRADD signaling induced 99. Vlantis K, Wullaert A, Polykratis A, et al. NEMO prevents RIP kinase 1- by TNF-receptor 1 and the Epstein-Barr virus oncoprotein LMP1. Biol mediated epithelial cell death and chronic intestinal inflammation Chem. 2008;389(10):1261–1271. by NF-κB-dependent and -independent functions. Immunity. 2016; 121. Luftig M, Yasui T, Soni V, et al. Epstein-Barr virus latent infec- 44(3):553–567. tion membrane protein 1 TRAF-binding site induces NIK/IKK 100. Tosello V, Bordin F, Yu J, et al. Calcineurin and GSK-3 inhibition α-dependent noncanonical NF-κB activation. Proc Natl Acad Sci sensitizes T-cell acute lymphoblastic leukemia cells to apoptosis U S A. 2004;101(1):141–146. through X-linked inhibitor of apoptosis protein degradation. Leukemia. 122. Takada H, Imadome KI, Shibayama H, et al. EBV induces persistent 2016;30(4):812–822. NF-κB activation and contributes to survival of EBV-positive neo- 101. Kwon HJ, Choi GE, Ryu S, et al. Stepwise phosphorylation of p65 plastic T- or NK-cells. PLoS One. 2017;12(3):e0174136. promotes NF-κB activation and NK cell responses during target cell 123. Kim SH, Ezhilarasan R, Phillips E, et al. Serine/threonine kinase recognition. Nat Commun. 2016;7:11686. MLK4 determines mesenchymal identity in glioma stem cells in an 102. Sau A, Lau R, Cabrita MA, et al. Persistent activation of NF-κB in NF-κB-dependent manner. Cancer Cell. 2016;29(2):201–213. BRCA1-dec fi ient mammary progenitors drives aberrant proliferation 124. Zhang J, Jia L, Lin W, et al. Epstein-Barr virus-encoded latent mem- and accumulation of DNA damage. Cell Stem Cell. 2016;19(1):52–65. brane protein 1 upregulates glucose transporter 1 transcription via the 103. Salazar L, Kashiwada T, Krejci P, et al. Fibroblast growth factor mTORC1/NF-κB signaling pathways. J Virol. 2017;91(6):e02168. receptor 3 interacts with and activates TGFβ-activated kinase 1 125. Dajee M, Lazarov M, Zhang JY, et al. NF-κB blockade and oncogenic tyrosine phosphorylation and NFκB signaling in multiple myeloma Ras trigger invasive human epidermal neoplasia. Nature. 2003; and bladder cancer. PLoS One. 2014;9(1):e86470. 421(6923):639–643. 104. Liu F, Bardhan K, Yang D, et al. NF-κB directly regulates Fas tran- 126. Luedde T, Beraza N, Kotsikoris V, et al. Deletion of NEMO/IKKγ scription to modulate Fas-mediated apoptosis and tumor suppression. in liver parenchymal cells causes steatohepatitis and hepatocellular J Biol Chem. 2012;287(30):25530–25540. carcinoma. Cancer Cell. 2007;11(2):119–132. 105. Ben-Neriah Y, Karin M. Inflammation meets cancer with NF- κB as 127. Sakurai T, He G, Matsuzawa A, et al. Hepatocyte necrosis induced by the matchmaker. Nat Immunol. 2011;12(8):715–723. oxidative stress and IL-1α release mediate carcinogen-induced com- 106. Grivennikov SI, Greten FR, Karin M. Immunity inflammation and pensatory proliferation and liver tumorigenesis. Cancer Cell. 2008; cancer. Cell. 2010;140(6):883–899. 14(2):156–165. 107. Smale ST. Hierarchies of NF-κB target-gene regulation. Nat Immunol. 128. Kohler UA, Böhm F, Rolfs F, et al. NF-κB/RelA and Nrf2 cooperate 2011;12(8):689–694. to maintain hepatocyte integrity and to prevent development of hepa- 108. Kiechl S, Wittmann J, Giaccari A, et al. Blockade of receptor activa- tocellular adenoma. J Hepatol. 2016;64(1):94–102. tor of nuclear factor-κB (RANKL) signaling improves hepatic insulin 129. Schreck R, Rieber P, Baeuerle PA. Reactive oxygen intermediates resistance and prevents development of diabetes mellitus. Nat Med. as apparently widely used messengers in the activation of the NF-κB 2013;19(3):358–363. transcription factor and HIV-1. EMBO J. 1991;10(8):2247–2258. 109. Kondegowda NG, Fenutria R, Pollack IR, et al. Osteoprotegerin and 130. Feng M, Feng J, Chen W, et al. Lipocalin 2 suppresses metastasis of denosumab stimulate human beta cell proliferation through inhibi- colorectal cancer by attenuating NF-κB-dependent activation of snail tion of the receptor activator of NF-κB ligand pathway. Cell Metab. and epithelial mesenchymal transition. Mol Cancer. 2016;15(1):77. 2015;22(1):77–85. 131. Kaur S, Sharma N, Krishn SR, et al. MUC4-mediated regulation of 110. Zanotto-Filho A, Gonçalves RM, Klafke K, et al. Inflammatory land - acute phase protein lipocalin 2 through HER2/AKT/NF-κB signaling scape of human brain tumors reveals an NFκB dependent cytokine in pancreatic cancer. Clin Cancer Res. 2014;20(3):688–700. pathway associated with mesenchymal glioblastoma. Cancer Lett. 132. Mahadevan NR, Rodvold J, Almanza G, Perez AF, Wheeler MC, 2017;390:176–187. Zanetti M. ER stress drives lipocalin 2 upregulation in prostate cancer 111. Son DS, Kabir SM, Dong Y, Lee E, Adunyah SE. Characteristics of cells in an NF-κB-dependent manner. BMC Cancer. 2011;11:229. chemokine signatures elicited by EGF and TNF in ovarian cancer 133. Shi Z, Hu Z, Chen D, et al. MicroRNA-200a mediates nasopharyn- cells. J Inflamm (Lond) . 2013;10(1):25. geal carcinoma cell proliferation through the activation of nuclear 112. Olson TS, Ley K. Chemokines and chemokine receptors in leukocyte factor-κB. Mol Med Rep. 2016;13(2):1732–1738. trafficking. Am J Physiol Regul Integr Comp Physiol. 2002;283(1): 134. Wang Y, Ren F, Wang Y, et al. CHIP/Stub1 functions as a tumor sup- R7–R28. pressor and represses NF-κB-mediated signaling in colorectal cancer. 113. Banerjee S, McGee DW. ROCK activity affects IL-1-induced signaling Carcinogenesis. 2014;35(5):983–991. possibly through MKK4 and p38 MAPK in Caco-2 cells. In Vitro Cell 135. Erstad DJ, Cusack JC Jr. Targeting the NF-κB pathway in cancer Dev Biol Anim. 2016;52(8):878–884. therapy. Surg Oncol Clin N Am. 2013;22(4):705–746. 114. Greten FR, Arkan MC, Bollrath J, et al. NF-κB is a negative regulator 136. Gupta SC, Sundaram C, Reuter S, Aggarwal BB. Inhibiting NF-κB of IL-1β secretion as revealed by genetic and pharmacological inhibi- activation by small molecules as a therapeutic strategy. Biochim tion of IKKβ. Cell. 2007;130(5):918–931. Biophys Acta. 2010;1799(10–12):775–787. 115. Gilmore TD. The Re1/NF-κB/IκB signal transduction pathway and 137. Castro AC, Dang LC, Soucy F, et al. Novel IKK inhibitors: cancer. Cancer Treat Res. 2003;115:241–265. β-carbolines. Bioorg Med Chem Lett. 2003;13(14):2419–2422. 116. Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature. 138. Gilmore TD, Herscovitch M. Inhibitors of NF-κB signaling:785 and 2009;458(7239):719–724. counting. Oncogene. 2006;25(51):6887–6899. submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 Dovepress Dovepress NFκB pathway in cancer 139. Wu CY, Ke Y, Zeng YF, Zhang YW, Yu HJ. Anticancer activity of 146. Qian C, Chen X, Qi Y, et al. Sporamin induces apoptosis and inhibits Astragalus polysaccharide in human non-small cell lung cancer cells. NF-κB activation in human pancreatic cancer cells. Tumour Biol. Cancer Cell Int. 2017;17:115. 2017;39(7):1010428317706917. 140. Jin R, Chen Q, Yao S, et al. Synthesis and anti-tumor activity of EF24 147. Oida K, Matsuda A, Jung K, et al. Nuclear factor-kB plays a critical analogues as IKKβ inhibitors. Eur J Med Chem. 2017;144:218–228. role in both intrinsic and acquired resistance against endocrine therapy 141. Zhang Y, Yang B, Zhao J, Li X, Zhang L, Zhai Z. Proteasome inhibitor in human breast cancer cells. Sci Rep. 2014;4:4057. carbobenzoxy-l-leucyl-l-leucyl-l-leucinal (MG132) enhances thera- 148. Chen F, Castranova V, Shi X. New insights into the role of nuclear peutic effect of paclitaxel on breast cancer by inhibiting nuclear factor factor-κB in cell growth regulation. Am J Pathol. 2001;159(2): (NF)-κB signaling. Med Sci Monit. 2018;24:294–304. 387–397. 142. Sun F, Zhang Y, Xu L, et al. Proteasome inhibitor MG132 enhances 149. Barbosa ML, da Conceicao RA, Fraga AG, et al. NF-κB signaling cisplatin-induced apoptosis in osteosarcoma cells and inhibits tumor pathway inhibitors as anticancer drug candidates. Anticancer Agents growth. Oncol Res. Epub 2017 Nov 30. Med Chem. 2017;17(4):483–490. 143. Vaisitti T, Gaudino F, Ouk S, et al. Targeting metabolism and survival 150. Capece D, Verzella D, Tessitore A, Alesse E, Capalbo C, Zazzeroni F. in chronic lymphocytic leukemia and Richter syndrome cells by a Cancer secretome and inflammation: the bright and the dark sides of novel NF-κB inhibitor. Haematologica. 2017;102(11):1878–1889. NF-κB. Semin Cell Dev Biol. Epub 2017 Aug 2. 144. Vu KT, Zhang F, Hulleman JD. Conditional genetically encoded small molecule-regulated inhibition of NFκB signaling in RPE cells. Invest Ophthalmol Vis Sci. 2017;58(10):4126–4137. 145. Pollock N, Taylor G, Jobe F, Guzman E. Modulation of the transcrip- tion factor NF-κB in antigen-presenting cells by bovine respiratory syncytial virus small hydrophobic protein. J Gen Virol. 2017;98(7): 1587–1599. OncoTargets and Therapy Dovepress Publish your work in this journal OncoTargets and Therapy is an international, peer-reviewed, open patient perspectives such as quality of life, adherence and satisfaction. access journal focusing on the pathological basis of all cancers, potential The manuscript management system is completely online and includes targets for therapy and treatment protocols employed to improve the a very quick and fair peer-review system, which is all easy to use. Visit management of cancer patients. The journal also focuses on the impact http://www.dovepress.com/testimonials.php to read real quotes from of management programs and new therapeutic agents and protocols on published authors. Submit your manuscript here: http://www.dovepress.com/oncotargets-and-therapy-journal submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 Dovepress

Journal

OncoTargets and therapy – Pubmed Central

Published: Apr 11, 2018

There are no references for this article.