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Deconvoluting the complexity of autophagy in colorectal cancer: From crucial pathways to targeted therapies

Deconvoluting the complexity of autophagy in colorectal cancer: From crucial pathways to targeted... TYPE Mini Review PUBLISHED 12 September 2022 DOI 10.3389/fonc.2022.1007509 Deconvoluting the complexity of autophagy in colorectal OPEN ACCESS EDITED BY Bo Liu, cancer: From crucial pathways Sichuan University, China REVIEWED BY to targeted therapies Lingjuan Zhu, Shenyang Pharmaceutical University, China 1 2 2 † † Liming Qiang , Hongpeng Li , Zhaohui Wang , Haiyang Yu,Tianjin University of Traditional Chinese Medicine, 2 2 Lin Wan and Guangfu Jiang China 1 2 Department of Gastroenterology Ward, Guang’an People’s Hospital, Guang’an, China, Department of Gastrointestinal Surgery, Guang’an People’s Hospital, Guang’an, China *CORRESPONDENCE Guangfu Jiang [email protected] These authors have contributed equally to this work Colorectal cancer (CRC) is a common gastrointestinal tumor with a high degree of malignancy, and most clinical cases are diagnosed at an advanced SPECIALTY SECTION This article was submitted to stage, which has unfortunately missed an opportunity for surgery; therefore, Pharmacology of Anti-Cancer Drugs, elucidation of the crucial pathways of CRC development and discovery of a section of the journal Frontiers in Oncology targeted therapeutic strategies should be anticipated. Autophagy, which is an evolutionarily highly conserved catabolic process, may promote tumorigenesis RECEIVED 30 July 2022 ACCEPTED 19 August 2022 and development of CRC. On the contrary, autophagy can trigger programmed PUBLISHED 12 September 2022 cell death to inhibit CRC progression. Correspondingly, several targeted CITATION therapeutic strategies have been reported in CRC, including small-molecule Qiang L, Li H, Wang Z, Wan L and compounds, polypeptides, non-coding RNAs, photodynamic, and adjuvant Jiang G (2022) Deconvoluting the complexity of autophagy in colorectal therapies. Thus, in this review, we focus on summarizing the crucial cancer: From crucial pathways to pathways of autophagy in CRC, and further discuss the current therapeutic targeted therapies. strategies targeting autophagy. Together, these findings may shed light on the Front. Oncol. 12:1007509. doi: 10.3389/fonc.2022.1007509 key regulatory mechanisms of autophagy and provide more promising COPYRIGHT therapeutic approaches for the future CRC therapies. © 2022 Qiang, Li, Wang, Wan and Jiang. This is an open-access article KEYWORDS distributed under the terms of the Creative Commons Attribution License colorectal cancer (CRC), autophagy, crucial pathway, therapeutic strategy, (CC BY). The use, distribution or targeted therapy reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Frontiers in Oncology 01 frontiersin.org Qiang et al. 10.3389/fonc.2022.1007509 GRAPHICAL ABSTRACT Of note, autophagy is an evolutionarily highly conserved Introduction catabolic process that regulates the expression of various oncogenes and tumor suppressor genes, which is a double-edged Colorectal cancer (CRC) is well-known as the most common sword in many types of human cancers, such as CRC (8). On one malignant gastrointestinal tumor in the world, with about 1.9 hand, autophagy plays a cytoprotective role by removing misfolded million new cases in 2020, accounting for about 10% of the global proteins, damaged organelles, and reactive oxygen species, limiting cancer incidence, ranking third among all cancers (1). And, CRC tumorigenesis; on the other hand, autophagy provides energy mortality constantly remains at a relatively high level, with about through catabolism to help tumor cells cope with stress stimuli, 940,000 new deaths in 2020, accounting for 9.4% of global cancer such as insufficient oxygen, nutrient deficiencies, or cancer deaths, which is the second leading cause of cancer death followed treatment, which leads to tumor progression (9, 10). Currently, by lung cancer (1, 2). The 5-year survival rate of CRC patients is there are some small-molecule compounds as autophagic approximately60%-70% withdistant stage diagnosis is only 14% (2, modulators (e.g., chloroquine or hydroxychloroquine) have 3). Unfortunately, the majority of CRC cases are usually detected in shown a promising tumor therapeutic potential in clinical trials, the advanced clinical stage and diagnosed as the distant stage with a and targeting autophagy has gradually been recognized as one of poor prognosis (3, 4). Hitherto, the current treatment of CRC has new strategies for potential therapeutic purposes (11). As still been limited to the traditional surgery combined with mentioned above, in this review, we summarize several crucial chemoradiotherapy (5); however, chemotherapy drugs, including pathways of autophagy in CRC progression, and further discuss the most classic 5-Fluorouracil (5-FU), will inevitably develop some therapeutic strategies targeting autophagy to improve chemotherapy resistance after long-term treatment, weakening CRC treatment. the efficacy and causing tumor recurrence (6). Due to the severe side effects of chemoradiotherapy and the inability of surgical treatment for patients diagnosed at an advanced stage, most Crucial pathways for autophagy patients, especially those with poor prognosis, still lack effective targeted therapy, resulting in a high annual mortality rate of CRC regulation in CRC (1, 2, 7). Thus, in-depth exploration of the pathogenesis of CRC and searching foreffective targeted therapeutic approaches are urgent to It is well-known that there are five critical stages in the be solved. canonical autophagy process, including autophagy initiation, Frontiers in Oncology 02 frontiersin.org Qiang et al. 10.3389/fonc.2022.1007509 phagophore nucleation, phagophore elongation and maturation, 1 (AMBRA1) and UV radiation resistance-associated (UVRAG), autophagosome and lysosome fusion, autolysosome degradation which is responsible for the phagophore nucleation; specifically, it is and recycling (12). usually phosphorylated by activated ULK1 and acts as an integral scaffold for the PI3K complex, recruiting autophagy-related proteins such as ATG9 to localize to phagophore (21). Interestingly, a recent Autophagy initiation: ULK1-ATG13- study has shown that the transcription factor sex-determining region FIP200-ATG101 Y-box2 (SOX2) can bind to the promoter of BECN1 to induce its transcription and activate autophagy in SW480 and SW620 human UNC-51-like autophagy-activating kinase 1 (ULK1), as the CRC cells, resulting in tumor progression (22); and, interleukin-6 (IL- homologous protein of yeast Atg1, plays a vital role in 6), independently of its substrate signal transducer and activator of the autophagy initiation stage. As a conserved promoter of the transcription 3 (STAT3), induces Janus kinase 2 (JAK2) to autophagy process, ULK1 forms ULK complex with autophagy- phosphorylate the tyrosine residue at position 333 of BECN1 in related gene (ATG) 13, RB1-inducible coiled-coil 1 (RB1CC1; LoVo human CRC cells, enhancing BECN1-VPS34 interaction and FIP200), and ATG101, which transmit autophagy signals and autophagy significantly, which leading to a poor prognosis of CRC initiate the formation of autophagosome when they are activated patients (23). In addition, the inhibition of VPS34 also strongly reduces (13). Recently, there is a study has shown that ULK1 is the most the level of autophagy in Caco-2 human CRC cells (24)(Figure 1). frequently mutated gene in The Cancer Genome Atlas (TCGA)- colorectal adenocarcinoma dataset, implying that ULK1 and its regulatory network may be closely related to colorectal Phagophore elongation and maturation: carcinogenesis (14). Notably, the upregulation of ULK1 ATG5-ATG12-ATG16L1/ATG4B-ATG7- significantly induces autophagy-dependent cell death in RKO LC3 human CRC cells, which exerts excellent antiproliferative potency (15). There are two important ubiquitination modifications in The mechanistic target of rapamycin (mTOR), the most phagophore elongation and maturation, one of which is that widely studied negative regulator of autophagy, is usually ATG5, ATG12 and ATG16L1 are catalyzed by ATG7 and activated by PI3K-Akt and directly inhibits ULK1 to inhibit ATG10 to form a complex and localize to the autophagosome autophagy (16). In CRC, FAT tumor suppressor homolog 4 membrane (25). In CRC, patients with high ATG5 expression (FAT4) inhibits the PI3K-Akt-mTOR pathway, promoting generally have a poorer prognosis and are more likely to cause T300A autophagy and inhibiting migration and invasion in SW480, tumor recurrence (26). Interestingly, the ATG16L1 variant HCT116 and LOVO human CRC cells (17); similarly, elicits a defect of autophagy, which is closely associated with downregulation of pleckstrin homology like domain family A better patient prognosis (27). Notably, ATG16L2, as a paralog of member 2 (PHLDA2) inhibits the PI3K-Akt-mTOR pathway, ATG16L1, which N-terminal region also binds to the ATG5- inducing autophagy and inhibiting proliferation in SW480, ATG12 complex like ATG16L1, but is not recruited to the HCT116 human CRC cells (18). autophagosome membrane, possibly acting as a potential AMP-activated protein kinase (AMPK) is also a critical competitive ATG16L1 inhibitor to inhibit autophagy; in CRC, regulator upstream of ULK1, which directly phosphorylates its overexpression inhibits tumor proliferation in vitro and in ULK1 to activate autophagy. In addition, activated AMPK also vivo, and is associated with usually a long survival rate (28). The phosphorylates downstream tuberous sclerosis complex 1 and 2 other ubiquitination modification is that ATG4B and ATG7 (TSC1/2) to enhance inhibition of Rheb, thereby inhibiting cleave the LC3 precursor protein to generate LC3-I, and the mTOR and inducing autophagy (19). In HCT116 and HT29 ATG5-ATG12-ATG16L1 complex catalyzes the coupling of human CRC cells, knockdown of AMPK restricted tumor LC3-I to phosphatidylethanolamine (PE) to form LC3-II autophagy-dependent cell death, leading to tumor progression (MAP1LC3B) (29). In HCT116 and Caco2 human CRC cells, (20)(Figure 1). silencing of ATG4B increases autophagy levels (30). ATG7 is usually highly expressed in CRC cells and has nothing to do with the survival of intestinal epithelial cells, but affects the survival of Phagophore nucleation: BECN1-VPS34- tumors, which is a potential target in CRC (31)(Figure 1). VPS15-ATG14-AMBRA1-UVRAG Coiled-coil myosin-like BCL2-interacting protein (BECN1), as the Autophagosome and lysosome fusion, homologous protein of yeast Atg6, forms the class III phosphoinositide autolysosome degradation and recycling 3-kinase (PI3K) complex with phosphatidylinositol 3-kinase catalytic subunittype3(PIK3C3;VPS34),phosphoinositide 3-kinase regulatory Ras-related protein Rab-7a (RAB7A) is a critical small subunit 4 (PIK3R4; VPS15), ATG14, autophagy and beclin 1 regulator GTPase that promotes autophagosome-lysosome fusion, which Frontiers in Oncology 03 frontiersin.org Qiang et al. 10.3389/fonc.2022.1007509 FIGURE 1 Crucial pathways of autophagy in CRC. Autophagy in CRC broadly contains five stages, namely autophagy initiation, phagophore nucleation, phagophore elongation and maturation, autophagosome and lysosome fusion, and autolysosome degradation and recycling. The ULK complex (ULK1-ATG13-FIP200-ATG101) triggers autophagy initiation and the PI3K complex (BECN1-VPS34-VPS15-ATG14-AMBRA1-UVRAG) promotes phagophore nucleation. Moreover, phagophore elongation and maturation contain two important ubiquitination modifications, one of which is the formation of complexes and localization of ATG5, ATG12, and ATG16L1 to the autophagosome membrane catalyzed by ATG7 and ATG10; the other is the cleavage of LC3 precursor protein by ATG4B and ATG7 to generate LC3-I, and the ATG5-ATG12-ATG16L1 complex catalyzes LC3-I coupling with PE to form LC3-II. Subsequently, RAB7A and LAMP1 are involved in autophagosome and lysosome fusion to form autolysosome. Finally, the contents of the autolysosome are degraded and recycled into the cytoplasm to re-engage in cellular metabolism. together with lysosome-associated membrane protein 1 Small-molecule compounds targeting (LAMP1), participates in autophagosome-lysosome fusion to autophagy form autolysosome. Subsequently, the contents of the autolysosome are degraded and recycled into the cytoplasm to Hitherto, a variety of small-molecule compounds have re-engage in cellular metabolism (25). Currently, sorting nexin demonstrated compelling efficacy in CRC therapy via modulating 10 (SNX10) has been reported to interact with ATG12-ATG5 autophagy. For instance, Fangchinoline, an alkaloid monomer with conjugates and LAMP1 to promote autophagosome-lysosome anti-inflammatory activity derived from the Stephaniae tetrandrine fusion, inhibiting the occurrence and progression of CRC S. Moore, is a novel autophagy agonist in CRC that activates the (32)(Figure 1). AMPK-mTOR-ULK1 pathway to induce autophagy-dependent cell death in HT29 and HCT116 human CRC cells and also exerts an effective growth inhibition of tumors in vivo (33). Therapeutic strategies targeting Similarly, Chaetocochin J, an alkaloid monomer derived from Chaetomium sp, activates AMPK and inhibits PI3K-Akt-mTOR autophagy for CRC therapy to induce autophagy, manifesting a solid antiproliferative effect in RKO, HCT116 and SW480 human CRC cells with IC s of 0.56, Currently, the therapeutic strategies for CRC are mainly traditional tumor treatment approaches, namely surgery, 0.61 and 0.65 mM(34). Celastrol, contained in Tripterygium wilfordii, inhibits the transcription factor Nur77 and upregulates radiotherapy, and chemotherapy. However, for patients whose conditions are not suitable for conventional treatment ATG7 to induce autophagy, achieving favorable antitumor effects in HCT116 and SW480 human CRC cells and the HCT116 approaches, such as patients with recurrent, metastatic tumors or locally advanced inoperable treatment, targeting autophagy with xenograft mouse model (35). Magnolin, a lignan monomer with anti-inflammatory and antioxidant activity derived from Magnolia small-molecule compounds has shown solid therapeutic potential. Notably, some emerging therapeutic strategies such as polypeptide biondii,significantly upregulates LC-3B and downregulates p62 by inhibiting leukemia inhibitory factor (LIF)- STAT3-Mcl-1 to and non-coding RNAs (ncRNAs) that modulate autophagy for CRC therapy also have achieved promising preclinical results. induce autophagy in HCT116 and SW480 human CRC cells and HCT116 xenograft model, which showing excellent anticancer Additionally, autophagy-targeting of photodynamic therapy and autophagy adjuvant chemotherapy strategies demonstrate the potential (36). Notably, Dehydrodiisoeugenol, a traditional Chinese medicine monomer composition derived from nutmeg, broad prospects of autophagy in CRC therapy. Frontiers in Oncology 04 frontiersin.org Qiang et al. 10.3389/fonc.2022.1007509 inhibits the late stage of autophagy by inducing endoplasmic to the occurrence and progression of diseases, especially cancer. reticulum (ER) stress, which greatly restricts the growth and Currently, there are a series of regulatory strategies have been proliferation of tumors; it exhibits convincing antiproliferative applied to tumor diagnosis and clinical trials (42). Notably, activity not only in HCT116 and SW620 human CRC cells with autophagy regulated by ncRNAs can affect multiple core IC sof54.32mM and 46.74mM but also in cell-derived xenograft processes involved in tumor survival, including proliferation, (CDX) and patient-derived tumor xenograft (PDX) models with apoptosis, invasion, and metastasis (43). Therefore, in-depth lower toxicity (37). In addition to natural products, there are several exploration of the mechanism of ncRNAs regulating autophagy repositioning small-molecule compounds that contribute to CRC is expected to provide new directions for CRC therapy. therapy via modulating autophagy. For instance, lomitapide, a Of note, microRNAs (miRNAs) are short ncRNAs that are clinical drug approved by the Food and Drug Administration extensively studied in cancer due to their modulation of various (FDA) for the treatment of hypercholesterolemia, is recently downstream mRNAs, which have been reported as novel specific reported to upregulate AMPK phosphorylation and promote the biomarkers in multiple cancers. For instance, miR-338-5p is formation of BECN1-VPS34-ATG14 complex, thereby inducing often highly expressed in the more malignant CRC phenotype, autophagy in HCT116 and HT29 human CRC cells, which implying that it could serve as a promising potential biomarker significantly inhibits tumor proliferation in vitro and in vivo (20). for CRC diagnosis; it inhibits PIK3C3 and suppresses autophagy Similarly, flubendazole, an anthelmintic drug approved by FDA, to promote tumor invasion and migration (44). Similarly, miR- downregulates STAT3 phosphorylation levels, mTOR and p62, and 27b-3p has also been reported as a potential therapeutic target upregulates Beclin 1 and LC3-I/II in HCT116, RKO and SW480 for CRC that suppresses autophagy by inhibiting ATG10, which human CRC cells, which promoting the initiation of autophagy to also helps reverse the resistance developed by long-term prevent tumor progression without substantially affecting normal chemotherapy (45)(Figure 2C). cell proliferation (38). Currently, a series of dual-target inhibitors of Notably, long non-coding RNAs (lncRNAs) modulate bromodomain-containing protein 4 (BRD4) and histone various biological processes, which are closely related to the deacetylases (HDAC) based on the structure design and occurrence and development of multiple diseases, and as a optimization have been reported, among which compound 17c is current research hotspot in cancer pathology. Metastasis- the most potent inhibitor of BRD4 and HDAC, induces autophagy associated lung adenocarcinoma transcript 1 (MALAT1), one via BRD4-AMPK-mTOR-ULK1 pathway, showing promising of the first lncRNAs reported to be involved in cancer metastasis, antiproliferative activities in vitro and in vivo (39)(Figure 2A). is aberrantly expressed in multiple human malignancies and can act as a sponge for various miRNAs. In CRC, MALAT1 acts as a sponge for miR-101 to activate autophagy, promoting Polypeptides targeting autophagy proliferation and inhibiting apoptosis in HCT116 and SW620 human CRC cells; therefore, the high expression of MALAT1 is Notably, compared with small-molecule compounds, closely related to poor prognosis in CRC patients (46). polypeptides usually have higher selectivity and stability in Interestingly, MALAT1 can also act as a sponge for miR-26a- vivo with a low probability of immune system rejection and 5p, reversing the inhibition of Smad1 by miR-26a-5p to elicit are expected to achieve higher efficacy. Recently, TD-3(TFM)3 Smad1 upregulation; Smad1 can bind to the ATG5 promoter, (FAS), a novel DNA tetrahedron (TD) with two types of induce the transcription of ATG5 to activate autophagy, therapeutic peptides (FAS peptides and FK-16 peptides) has promoting proliferation and metastasis in HT29 and SW1116 been designed; among them, FK-16 is delivered to the cytoplasm human CRC cells (47). Similarly, lncRNA small nucleolar RNA of HT-29 human CRC cells by cell-penetrating peptide, further host gene 6 (SNHG6) acts as a sponge for miR-26a-5p, upregulating the expression of p53, ATG5, and ATG7, inducing upregulating ULK1 and activating autophagy in RKO, HT29 autophagy-dependent cell death and exerting strong and specific and HCT116 human CRC cells (48). In addition, lncRNA small tumor-suppressive efficacy (40)(Figure 2B). In addition, LL-37, nucleolar RNA host gene 14 (SNHG14) is often highly expressed an antimicrobial peptide, is closely related to cellular processes in a variety of cancers, leading to poor progression; in CRC, such as apoptosis and autophagy, inhibiting the carcinogenesis SNHG14 suppresses miR-186 to upregulate ATG14, inducing of intestinal cells. However, due to the complex pathogenesis of autophagy in SW620 and SW480 human CRC cells (49). Cancer CRC, whether LL-37 can treat CRC by regulating autophagy still susceptibility candidate 9 (CASC9) is a lncRNA highly expressed need to explore (41). in CRC in both TCGA and The Encyclopedia of RNA Interactomes (ENCORI) datasets, which high expression is associated with poor patient prognosis. Inhibition of CASC9 Noncoding RNAs targeting autophagy upregulates the phosphorylation level of AMPK and suppresses Akt-mTOR signaling, inhibiting tumor growth and inducing In recent years, ncRNA has been found to play critical roles autophagy in HCT116 and SW480 human CRC cells, which is a promising strategy for CRC therapy (50). Moreover, lncRNA in various cellular physiological processes and is closely related Frontiers in Oncology 05 frontiersin.org Qiang et al. 10.3389/fonc.2022.1007509 A B FIGURE 2 Therapeutic strategies targeting autophagy for CRC therapy. (A–C) Small-molecule compounds, polypeptide, and ncRNAs for targeting autophagy in CRC therapy. Various small-molecule compounds, the polypeptide, and multiple ncRNAs modulate critical regulators of autophagy to treat CRC. (D) Photodynamic therapy targeting autophagy in CRC therapy. Multiple photosensitizers with specific wavelength light source irradiation induce autophagy-associated cell death, participating in CRC therapy. (E) Adjuvant chemotherapy by autophagy for CRC therapy. Autophagy inhibitors can effectively suppress the cytoprotective autophagy triggered by long-term chemotherapy and restore the sensitivity of tumors to chemotherapy drugs, enhancing the effectiveness of chemotherapy. functional intergenic repeating RNA element (FIRRE) is often downstream Bcl-2 to suppress beclin1 to inhibit autophagy in located in the nucleus and can bind PTBP1 to promote its vitro and in vivo (53)(Figure 2C). Although the application of translocation to the cytoplasm to stabilize the cytoplasmic ncRNAs in tumor diagnosis and treatment is still in the early mRNA BECN1, increasing the level of autophagy in RKO stage, as more and more mechanisms are discovered, we believe human CRC cells (51)(Figure 2C). that the clinical application of ncRNAs is just around the corner. Importantly, circular RNAs (circRNAs) are a special class of ncRNAs that often function as competing endogenous RNAs (ceRNAs) for miRNAs, which implied an emerging strategy in Photodynamic therapy targeting cancer therapy. For instance, circCUL2 acts as a sponge for miR- autophagy 208a-3p to inhibit tumor proliferation via upregulating protein phosphatase 6 catalytic subunit (PPP6C), which induces Photodynamic therapy (PDT), an emerging minimally autophagy in SW480 and SW620 human CRC cells and the invasive procedure for cancer therapy, relies on specific SW480 xenograft model (52). Similarly, circHIPK3 acts as a wavelength light source irradiation to activate photosensitizers sponge for miR-637 to upregulate STAT3, activating in tumors to generate biotoxic singlet oxygen and other highly Frontiers in Oncology 06 frontiersin.org Qiang et al. 10.3389/fonc.2022.1007509 reactive oxygen species (ROS), which in turn oxidatively xenografts (60). In addition, knockdown of ATG7 resensitizes damages tumors, and exerts therapeutic effects by inducing SW480 and HT29 human CRC cells to Irinotecan and 5-FU, various forms of cell death such as apoptosis or autophagy overcoming chemoresistance, again confirming the feasibility of (54, 55). Compared with traditional treatment strategies for autophagy inhibitors to alleviate chemoresistance (31). Similarly, cancer, PDT is less invasive, has better selectivity and a inhibition of autophagy also increases radiosensitivity, which broader range of applications, and can be repeated multiple implies a potential CRC therapeutic strategy. For instance, times without drug resistance or toxicity (55). Currently, PDT to downregulation of long non-coding RNA homeobox transcript induce autophagy has achieved a series of progress in CRC antisense intergenic RNA (HOTAIR) upregulates miR-93 to therapy. For instance, treatment of HCT116 and SW480 human downregulate ATG12, improving the effect of radiotherapy via CRC cells with the second-generation photosensitizers meta- inhibiting autophagy in SW480 and HCT116 human CRC cells tetrahydroxyphenylchlorin (m-THPC) and verteporfin(VP) and CRC xenograft models (61)(Figure 2E). produces a large amount of ROS, induces autophagy by activating c-Jun N-terminal kinase (JNK) and inhibiting the phosphorylation of mTOR; in addition, m-THPC and VP also Conclusions and perspectives effectively suppress the tumor progression of HCT116 xenografts (56). Importantly, both high-speed and short-term CRC is a common malignant tumor with a high global acute PDT (aPDT) and low-speed and long-term metronomic incidence and mortality rate, and its therapeutic strategies have PDT (mPDT) with the photosensitizer 5-aminolevulinic acid been mainly dependent on surgery, radiotherapy, and (ALA) can induce autophagy in SW837 human CRC cells, and chemotherapy so far. Unfortunately, some patients are already ALA-mPDT induces autophagy earlier and exhibits stronger at an advanced stage of CRC when they are detected and cannot antitumor effect than ALA-aPDT (57). Similarly, PDT with the be treated surgically. Therefore, development of some new photosensitizer zinc phthalocyanine (ZnPc) at a light flux of 12 emerging therapeutic approaches should be urgent. On one 2 2 J/cm or 24 J/cm induces autophagy in SW480 human CRC hand, autophagy removes damaged nucleic acids and cellular cells (58)(Figure 2D). organelles to protect cells from stress damage, effectively reducing the probability of CRC occurrence. On the other hand, autophagy may help CRC respond to the therapeutic Adjuvant chemotherapy targeting stimuli, provides the energy required for tumor proliferation autophagy through catabolism, and even resists drug stimuli to resistance. Notably, the crucial pathway for autophagy regulation is one 5-FU is the first drug recognized as an effective chemotherapy of the current research hotspots in CRC pathology. Many drug for CRC, which has been widely used in CRC clinical therapy canonical regulators of autophagy processes (e.g., ULK1, since 1957. Unfortunately, long-term treatment inevitably develops ATG5, ATG16L1) are aberrantly expressed in CRC patients. chemoresistance, resulting in tumor relapse; notably, autophagy In addition, some studies knocked down or overexpressed plays a critical role in its drug resistance mechanism. Once 5-FU critical regulators in each stage of autophagy to rationally gives tumors stress, autophagy can provide additional nutrients to utilize its two sides, initially showing favorable antitumor meet the metabolic needs of tumors, resulting in abnormal effects. In short, an in-depth exploration of crucial pathways proliferation and weakening the effectiveness of chemotherapy for autophagy regulation in CRC and the corresponding effective (6). Therefore, the therapeutic strategy of 5-FU combined with interventions will considerably improve CRC therapy. autophagy inhibition may considerably improve the survival rate Currently, several small-molecule compounds targeting of CRC patients. For instance, the treatment of 5-FU decreases the autophagy (e.g., Fangchinoline, Chaetocochin J, and Celastrol) expression of serine hydroxymethyltransferase-2 (SHMT2), which have been achieving some promising preclinical results and promotes autophagy and triggers 5-FU resistance, resulting in poor exerted a great potential on potential CRC therapies. Notably, prognosis of CRC patients; while 5-FU combined with the compared with small-molecule compounds, polypeptides [e.g., autophagy inhibitor chloroquine (CQ) reverses the insensitivity TD-3(TFM)3(FAS)] generally have higher selectivity and to 5-FU in CRC cells with low SHMT2 expression in vitro and in stability in vivo, and are less susceptible to rejection by the vivo, thereby enhancing the effect of chemotherapy (59). immune system, exhibiting high therapeutic potential for CRC. Prodigiosin, a secondary metabolite synthesized by bacteria such In addition, some key regulatory factors (e.g., microRNA miR- as Serratia marcescens, inhibits autophagy by blocking the fusion of 338-5p, lncRNA MALAT1, and circRNA circCUL2) have also autophagosome and lysosome and suppressing the activity of been continuously identified as autophagy-related biomarkers in lysosomal hydrolase, further triggers the accumulation of LC3B- CRC, providing accumulating evidence for the availability of II and SQSTM, enhances the sensitivity of tumors to 5-FU, clinical diagnosis and treatment. As a new emerging therapeutic synergizing with 5-FU to inhibit CRC progression in HCT116 strategy, photodynamic therapy also achieved inspiring stage and SW480 human CRC cells and HCT116 cells nude mice results in CRC therapy by inducing autophagy, which provides Frontiers in Oncology 07 frontiersin.org Qiang et al. 10.3389/fonc.2022.1007509 more options for CRC patients. Interestingly, autophagy reverses Funding long-term chemotherapy-induced resistance and sensitize tumors to chemotherapeutic drugs. This work was supported by grants from the fund of the In summary, modulating autophagy has been emerging as a high-quality development of Guang ‘an People’s Hospital (Grant promising strategy for CRC therapy, which can benefit the No. 21FZ008). patients who are not suitable for traditional treatment, and can be used as adjuvant chemotherapy to overcome drug resistance. Importantly, the rapid development of new technologies, such as Conflict of interest artificial intelligence (AI) seems to be delineated the intricate dynamic balance of autophagy between CRC progression and The authors declare that the research was conducted in the treatment (62). With the continuous exploration of the absence of any commercial or financial relationships that could relationship between autophagy and CRC, we believe that the be construed as a potential conflict of interest. Janus roles of autophagy would be subtly manipulated, and more effectively therapeutic strategies will be exploited to greatly improve potential CRC therapies in the future. Publisher’s note Author contributions All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated LQ, HL participates in manuscript writing and figure organizations, or those of the publisher, the editors and the drawing; ZW, LW participates in references collection and reviewers. Any product that may be evaluated in this article, or manuscript formatting adjustments. GJ reviewed and edited claim that may be made by its manufacturer, is not guaranteed the manuscript. 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(2019) 179(5):1033–55. doi: 10.1016/j.cell.2019.10.017 doi: 10.1158/2159-8290.Cd-21-0090 Frontiers in Oncology 09 frontiersin.org Qiang et al. 10.3389/fonc.2022.1007509 Continued Glossary lncRNA long non-coding RNA MALAT1 metastasis-associated lung adenocarcinoma transcript 1 miRNAs microRNAs 5-FU 5-Fluorouracil mPDT metronomic PDT AI artificial intelligence mTOR mechanistic target of rapamycin ALA 5-aminolevulinic acid m-THPC meta-tetrahydroxyphenylchlorin AMBRA1 autophagy and beclin 1 regulator 1 ncRNA non-coding RNA AMPK AMP-activated protein kinase PDT photodynamic therapy aPDT acute PDT PDX patient-derived tumor xenograft ATG autophagy-related gene PE phosphatidylethanolamine BECN1 coiled-coil myosin-like BCL2-interacting protein PHLDA2 pleckstrin homology like domain family A member 2 BRD4 bromodomain-containing protein 4 PI3K phosphoinositide 3-kinase CASC9 cancer susceptibility candidate 9 PIK3C3 phosphatidylinositol 3-kinase catalytic subunit type 3 CDX cell-derived xenograft PIK3R4 phosphoinositide 3-kinase regulatory subunit 4 ceRNA competing endogenous RNA PPP6C protein phosphatase 6 catalytic subunit circRNA circular RNA RAB7A Ras-related protein Rab-7a CQ chloroquine RB1CC1 RB1-inducible coiled-coil 1 CRC colorectal cancer ROS reactive oxygen species ENCORI The Encyclopedia of RNA Interactomes SHMT2 serine hydroxymethyltransferase-2 ER endoplasmic reticulum SNHG6 small nucleolar RNA host gene 6 FAT4 FAT tumor suppressor homolog 4 SNHG14 small nucleolar RNA host gene 14 FDA Food and Drug Administration SNX10 sorting nexin 10 FIRRE functional intergenic repeating RNA element SOX2 sex-determining region Y-box2 HDAC histone deacetylases STAT3 signal transducer and activator of transcription 3 HOTAIR homeobox transcript antisense intergenic RNA TCGA The Cancer Genome Atlas IL-6 interleukin-6 TD tetrahedron JAK2 Janus kinase 2 TSC1/2 tuberous sclerosis complex 1 and 2 JNK c-Jun N-terminal kinase ULK1 UNC-51-like autophagy-activating kinase 1 LAMP1 lysosome-associated membrane protein 1 UVRAG UV radiation resistance-associated LIF leukemia inhibitory factor VP verteporfin ZnPc zinc phthalocyanine. (Continued) Frontiers in Oncology 10 frontiersin.org http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Frontiers in Oncology Unpaywall

Deconvoluting the complexity of autophagy in colorectal cancer: From crucial pathways to targeted therapies

Qiang, Liming; Li, Hongpeng; Wang, Zhaohui; Wan, Lin; Jiang, Guangfu
Frontiers in Oncology – Sep 12, 2022
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TYPE Mini Review PUBLISHED 12 September 2022 DOI 10.3389/fonc.2022.1007509 Deconvoluting the complexity of autophagy in colorectal OPEN ACCESS EDITED BY Bo Liu, cancer: From crucial pathways Sichuan University, China REVIEWED BY to targeted therapies Lingjuan Zhu, Shenyang Pharmaceutical University, China 1 2 2 † † Liming Qiang , Hongpeng Li , Zhaohui Wang , Haiyang Yu,Tianjin University of Traditional Chinese Medicine, 2 2 Lin Wan and Guangfu Jiang China 1 2 Department of Gastroenterology Ward, Guang’an People’s Hospital, Guang’an, China, Department of Gastrointestinal Surgery, Guang’an People’s Hospital, Guang’an, China *CORRESPONDENCE Guangfu Jiang [email protected] These authors have contributed equally to this work Colorectal cancer (CRC) is a common gastrointestinal tumor with a high degree of malignancy, and most clinical cases are diagnosed at an advanced SPECIALTY SECTION This article was submitted to stage, which has unfortunately missed an opportunity for surgery; therefore, Pharmacology of Anti-Cancer Drugs, elucidation of the crucial pathways of CRC development and discovery of a section of the journal Frontiers in Oncology targeted therapeutic strategies should be anticipated. Autophagy, which is an evolutionarily highly conserved catabolic process, may promote tumorigenesis RECEIVED 30 July 2022 ACCEPTED 19 August 2022 and development of CRC. On the contrary, autophagy can trigger programmed PUBLISHED 12 September 2022 cell death to inhibit CRC progression. Correspondingly, several targeted CITATION therapeutic strategies have been reported in CRC, including small-molecule Qiang L, Li H, Wang Z, Wan L and compounds, polypeptides, non-coding RNAs, photodynamic, and adjuvant Jiang G (2022) Deconvoluting the complexity of autophagy in colorectal therapies. Thus, in this review, we focus on summarizing the crucial cancer: From crucial pathways to pathways of autophagy in CRC, and further discuss the current therapeutic targeted therapies. strategies targeting autophagy. Together, these findings may shed light on the Front. Oncol. 12:1007509. doi: 10.3389/fonc.2022.1007509 key regulatory mechanisms of autophagy and provide more promising COPYRIGHT therapeutic approaches for the future CRC therapies. © 2022 Qiang, Li, Wang, Wan and Jiang. This is an open-access article KEYWORDS distributed under the terms of the Creative Commons Attribution License colorectal cancer (CRC), autophagy, crucial pathway, therapeutic strategy, (CC BY). The use, distribution or targeted therapy reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Frontiers in Oncology 01 frontiersin.org Qiang et al. 10.3389/fonc.2022.1007509 GRAPHICAL ABSTRACT Of note, autophagy is an evolutionarily highly conserved Introduction catabolic process that regulates the expression of various oncogenes and tumor suppressor genes, which is a double-edged Colorectal cancer (CRC) is well-known as the most common sword in many types of human cancers, such as CRC (8). On one malignant gastrointestinal tumor in the world, with about 1.9 hand, autophagy plays a cytoprotective role by removing misfolded million new cases in 2020, accounting for about 10% of the global proteins, damaged organelles, and reactive oxygen species, limiting cancer incidence, ranking third among all cancers (1). And, CRC tumorigenesis; on the other hand, autophagy provides energy mortality constantly remains at a relatively high level, with about through catabolism to help tumor cells cope with stress stimuli, 940,000 new deaths in 2020, accounting for 9.4% of global cancer such as insufficient oxygen, nutrient deficiencies, or cancer deaths, which is the second leading cause of cancer death followed treatment, which leads to tumor progression (9, 10). Currently, by lung cancer (1, 2). The 5-year survival rate of CRC patients is there are some small-molecule compounds as autophagic approximately60%-70% withdistant stage diagnosis is only 14% (2, modulators (e.g., chloroquine or hydroxychloroquine) have 3). Unfortunately, the majority of CRC cases are usually detected in shown a promising tumor therapeutic potential in clinical trials, the advanced clinical stage and diagnosed as the distant stage with a and targeting autophagy has gradually been recognized as one of poor prognosis (3, 4). Hitherto, the current treatment of CRC has new strategies for potential therapeutic purposes (11). As still been limited to the traditional surgery combined with mentioned above, in this review, we summarize several crucial chemoradiotherapy (5); however, chemotherapy drugs, including pathways of autophagy in CRC progression, and further discuss the most classic 5-Fluorouracil (5-FU), will inevitably develop some therapeutic strategies targeting autophagy to improve chemotherapy resistance after long-term treatment, weakening CRC treatment. the efficacy and causing tumor recurrence (6). Due to the severe side effects of chemoradiotherapy and the inability of surgical treatment for patients diagnosed at an advanced stage, most Crucial pathways for autophagy patients, especially those with poor prognosis, still lack effective targeted therapy, resulting in a high annual mortality rate of CRC regulation in CRC (1, 2, 7). Thus, in-depth exploration of the pathogenesis of CRC and searching foreffective targeted therapeutic approaches are urgent to It is well-known that there are five critical stages in the be solved. canonical autophagy process, including autophagy initiation, Frontiers in Oncology 02 frontiersin.org Qiang et al. 10.3389/fonc.2022.1007509 phagophore nucleation, phagophore elongation and maturation, 1 (AMBRA1) and UV radiation resistance-associated (UVRAG), autophagosome and lysosome fusion, autolysosome degradation which is responsible for the phagophore nucleation; specifically, it is and recycling (12). usually phosphorylated by activated ULK1 and acts as an integral scaffold for the PI3K complex, recruiting autophagy-related proteins such as ATG9 to localize to phagophore (21). Interestingly, a recent Autophagy initiation: ULK1-ATG13- study has shown that the transcription factor sex-determining region FIP200-ATG101 Y-box2 (SOX2) can bind to the promoter of BECN1 to induce its transcription and activate autophagy in SW480 and SW620 human UNC-51-like autophagy-activating kinase 1 (ULK1), as the CRC cells, resulting in tumor progression (22); and, interleukin-6 (IL- homologous protein of yeast Atg1, plays a vital role in 6), independently of its substrate signal transducer and activator of the autophagy initiation stage. As a conserved promoter of the transcription 3 (STAT3), induces Janus kinase 2 (JAK2) to autophagy process, ULK1 forms ULK complex with autophagy- phosphorylate the tyrosine residue at position 333 of BECN1 in related gene (ATG) 13, RB1-inducible coiled-coil 1 (RB1CC1; LoVo human CRC cells, enhancing BECN1-VPS34 interaction and FIP200), and ATG101, which transmit autophagy signals and autophagy significantly, which leading to a poor prognosis of CRC initiate the formation of autophagosome when they are activated patients (23). In addition, the inhibition of VPS34 also strongly reduces (13). Recently, there is a study has shown that ULK1 is the most the level of autophagy in Caco-2 human CRC cells (24)(Figure 1). frequently mutated gene in The Cancer Genome Atlas (TCGA)- colorectal adenocarcinoma dataset, implying that ULK1 and its regulatory network may be closely related to colorectal Phagophore elongation and maturation: carcinogenesis (14). Notably, the upregulation of ULK1 ATG5-ATG12-ATG16L1/ATG4B-ATG7- significantly induces autophagy-dependent cell death in RKO LC3 human CRC cells, which exerts excellent antiproliferative potency (15). There are two important ubiquitination modifications in The mechanistic target of rapamycin (mTOR), the most phagophore elongation and maturation, one of which is that widely studied negative regulator of autophagy, is usually ATG5, ATG12 and ATG16L1 are catalyzed by ATG7 and activated by PI3K-Akt and directly inhibits ULK1 to inhibit ATG10 to form a complex and localize to the autophagosome autophagy (16). In CRC, FAT tumor suppressor homolog 4 membrane (25). In CRC, patients with high ATG5 expression (FAT4) inhibits the PI3K-Akt-mTOR pathway, promoting generally have a poorer prognosis and are more likely to cause T300A autophagy and inhibiting migration and invasion in SW480, tumor recurrence (26). Interestingly, the ATG16L1 variant HCT116 and LOVO human CRC cells (17); similarly, elicits a defect of autophagy, which is closely associated with downregulation of pleckstrin homology like domain family A better patient prognosis (27). Notably, ATG16L2, as a paralog of member 2 (PHLDA2) inhibits the PI3K-Akt-mTOR pathway, ATG16L1, which N-terminal region also binds to the ATG5- inducing autophagy and inhibiting proliferation in SW480, ATG12 complex like ATG16L1, but is not recruited to the HCT116 human CRC cells (18). autophagosome membrane, possibly acting as a potential AMP-activated protein kinase (AMPK) is also a critical competitive ATG16L1 inhibitor to inhibit autophagy; in CRC, regulator upstream of ULK1, which directly phosphorylates its overexpression inhibits tumor proliferation in vitro and in ULK1 to activate autophagy. In addition, activated AMPK also vivo, and is associated with usually a long survival rate (28). The phosphorylates downstream tuberous sclerosis complex 1 and 2 other ubiquitination modification is that ATG4B and ATG7 (TSC1/2) to enhance inhibition of Rheb, thereby inhibiting cleave the LC3 precursor protein to generate LC3-I, and the mTOR and inducing autophagy (19). In HCT116 and HT29 ATG5-ATG12-ATG16L1 complex catalyzes the coupling of human CRC cells, knockdown of AMPK restricted tumor LC3-I to phosphatidylethanolamine (PE) to form LC3-II autophagy-dependent cell death, leading to tumor progression (MAP1LC3B) (29). In HCT116 and Caco2 human CRC cells, (20)(Figure 1). silencing of ATG4B increases autophagy levels (30). ATG7 is usually highly expressed in CRC cells and has nothing to do with the survival of intestinal epithelial cells, but affects the survival of Phagophore nucleation: BECN1-VPS34- tumors, which is a potential target in CRC (31)(Figure 1). VPS15-ATG14-AMBRA1-UVRAG Coiled-coil myosin-like BCL2-interacting protein (BECN1), as the Autophagosome and lysosome fusion, homologous protein of yeast Atg6, forms the class III phosphoinositide autolysosome degradation and recycling 3-kinase (PI3K) complex with phosphatidylinositol 3-kinase catalytic subunittype3(PIK3C3;VPS34),phosphoinositide 3-kinase regulatory Ras-related protein Rab-7a (RAB7A) is a critical small subunit 4 (PIK3R4; VPS15), ATG14, autophagy and beclin 1 regulator GTPase that promotes autophagosome-lysosome fusion, which Frontiers in Oncology 03 frontiersin.org Qiang et al. 10.3389/fonc.2022.1007509 FIGURE 1 Crucial pathways of autophagy in CRC. Autophagy in CRC broadly contains five stages, namely autophagy initiation, phagophore nucleation, phagophore elongation and maturation, autophagosome and lysosome fusion, and autolysosome degradation and recycling. The ULK complex (ULK1-ATG13-FIP200-ATG101) triggers autophagy initiation and the PI3K complex (BECN1-VPS34-VPS15-ATG14-AMBRA1-UVRAG) promotes phagophore nucleation. Moreover, phagophore elongation and maturation contain two important ubiquitination modifications, one of which is the formation of complexes and localization of ATG5, ATG12, and ATG16L1 to the autophagosome membrane catalyzed by ATG7 and ATG10; the other is the cleavage of LC3 precursor protein by ATG4B and ATG7 to generate LC3-I, and the ATG5-ATG12-ATG16L1 complex catalyzes LC3-I coupling with PE to form LC3-II. Subsequently, RAB7A and LAMP1 are involved in autophagosome and lysosome fusion to form autolysosome. Finally, the contents of the autolysosome are degraded and recycled into the cytoplasm to re-engage in cellular metabolism. together with lysosome-associated membrane protein 1 Small-molecule compounds targeting (LAMP1), participates in autophagosome-lysosome fusion to autophagy form autolysosome. Subsequently, the contents of the autolysosome are degraded and recycled into the cytoplasm to Hitherto, a variety of small-molecule compounds have re-engage in cellular metabolism (25). Currently, sorting nexin demonstrated compelling efficacy in CRC therapy via modulating 10 (SNX10) has been reported to interact with ATG12-ATG5 autophagy. For instance, Fangchinoline, an alkaloid monomer with conjugates and LAMP1 to promote autophagosome-lysosome anti-inflammatory activity derived from the Stephaniae tetrandrine fusion, inhibiting the occurrence and progression of CRC S. Moore, is a novel autophagy agonist in CRC that activates the (32)(Figure 1). AMPK-mTOR-ULK1 pathway to induce autophagy-dependent cell death in HT29 and HCT116 human CRC cells and also exerts an effective growth inhibition of tumors in vivo (33). Therapeutic strategies targeting Similarly, Chaetocochin J, an alkaloid monomer derived from Chaetomium sp, activates AMPK and inhibits PI3K-Akt-mTOR autophagy for CRC therapy to induce autophagy, manifesting a solid antiproliferative effect in RKO, HCT116 and SW480 human CRC cells with IC s of 0.56, Currently, the therapeutic strategies for CRC are mainly traditional tumor treatment approaches, namely surgery, 0.61 and 0.65 mM(34). Celastrol, contained in Tripterygium wilfordii, inhibits the transcription factor Nur77 and upregulates radiotherapy, and chemotherapy. However, for patients whose conditions are not suitable for conventional treatment ATG7 to induce autophagy, achieving favorable antitumor effects in HCT116 and SW480 human CRC cells and the HCT116 approaches, such as patients with recurrent, metastatic tumors or locally advanced inoperable treatment, targeting autophagy with xenograft mouse model (35). Magnolin, a lignan monomer with anti-inflammatory and antioxidant activity derived from Magnolia small-molecule compounds has shown solid therapeutic potential. Notably, some emerging therapeutic strategies such as polypeptide biondii,significantly upregulates LC-3B and downregulates p62 by inhibiting leukemia inhibitory factor (LIF)- STAT3-Mcl-1 to and non-coding RNAs (ncRNAs) that modulate autophagy for CRC therapy also have achieved promising preclinical results. induce autophagy in HCT116 and SW480 human CRC cells and HCT116 xenograft model, which showing excellent anticancer Additionally, autophagy-targeting of photodynamic therapy and autophagy adjuvant chemotherapy strategies demonstrate the potential (36). Notably, Dehydrodiisoeugenol, a traditional Chinese medicine monomer composition derived from nutmeg, broad prospects of autophagy in CRC therapy. Frontiers in Oncology 04 frontiersin.org Qiang et al. 10.3389/fonc.2022.1007509 inhibits the late stage of autophagy by inducing endoplasmic to the occurrence and progression of diseases, especially cancer. reticulum (ER) stress, which greatly restricts the growth and Currently, there are a series of regulatory strategies have been proliferation of tumors; it exhibits convincing antiproliferative applied to tumor diagnosis and clinical trials (42). Notably, activity not only in HCT116 and SW620 human CRC cells with autophagy regulated by ncRNAs can affect multiple core IC sof54.32mM and 46.74mM but also in cell-derived xenograft processes involved in tumor survival, including proliferation, (CDX) and patient-derived tumor xenograft (PDX) models with apoptosis, invasion, and metastasis (43). Therefore, in-depth lower toxicity (37). In addition to natural products, there are several exploration of the mechanism of ncRNAs regulating autophagy repositioning small-molecule compounds that contribute to CRC is expected to provide new directions for CRC therapy. therapy via modulating autophagy. For instance, lomitapide, a Of note, microRNAs (miRNAs) are short ncRNAs that are clinical drug approved by the Food and Drug Administration extensively studied in cancer due to their modulation of various (FDA) for the treatment of hypercholesterolemia, is recently downstream mRNAs, which have been reported as novel specific reported to upregulate AMPK phosphorylation and promote the biomarkers in multiple cancers. For instance, miR-338-5p is formation of BECN1-VPS34-ATG14 complex, thereby inducing often highly expressed in the more malignant CRC phenotype, autophagy in HCT116 and HT29 human CRC cells, which implying that it could serve as a promising potential biomarker significantly inhibits tumor proliferation in vitro and in vivo (20). for CRC diagnosis; it inhibits PIK3C3 and suppresses autophagy Similarly, flubendazole, an anthelmintic drug approved by FDA, to promote tumor invasion and migration (44). Similarly, miR- downregulates STAT3 phosphorylation levels, mTOR and p62, and 27b-3p has also been reported as a potential therapeutic target upregulates Beclin 1 and LC3-I/II in HCT116, RKO and SW480 for CRC that suppresses autophagy by inhibiting ATG10, which human CRC cells, which promoting the initiation of autophagy to also helps reverse the resistance developed by long-term prevent tumor progression without substantially affecting normal chemotherapy (45)(Figure 2C). cell proliferation (38). Currently, a series of dual-target inhibitors of Notably, long non-coding RNAs (lncRNAs) modulate bromodomain-containing protein 4 (BRD4) and histone various biological processes, which are closely related to the deacetylases (HDAC) based on the structure design and occurrence and development of multiple diseases, and as a optimization have been reported, among which compound 17c is current research hotspot in cancer pathology. Metastasis- the most potent inhibitor of BRD4 and HDAC, induces autophagy associated lung adenocarcinoma transcript 1 (MALAT1), one via BRD4-AMPK-mTOR-ULK1 pathway, showing promising of the first lncRNAs reported to be involved in cancer metastasis, antiproliferative activities in vitro and in vivo (39)(Figure 2A). is aberrantly expressed in multiple human malignancies and can act as a sponge for various miRNAs. In CRC, MALAT1 acts as a sponge for miR-101 to activate autophagy, promoting Polypeptides targeting autophagy proliferation and inhibiting apoptosis in HCT116 and SW620 human CRC cells; therefore, the high expression of MALAT1 is Notably, compared with small-molecule compounds, closely related to poor prognosis in CRC patients (46). polypeptides usually have higher selectivity and stability in Interestingly, MALAT1 can also act as a sponge for miR-26a- vivo with a low probability of immune system rejection and 5p, reversing the inhibition of Smad1 by miR-26a-5p to elicit are expected to achieve higher efficacy. Recently, TD-3(TFM)3 Smad1 upregulation; Smad1 can bind to the ATG5 promoter, (FAS), a novel DNA tetrahedron (TD) with two types of induce the transcription of ATG5 to activate autophagy, therapeutic peptides (FAS peptides and FK-16 peptides) has promoting proliferation and metastasis in HT29 and SW1116 been designed; among them, FK-16 is delivered to the cytoplasm human CRC cells (47). Similarly, lncRNA small nucleolar RNA of HT-29 human CRC cells by cell-penetrating peptide, further host gene 6 (SNHG6) acts as a sponge for miR-26a-5p, upregulating the expression of p53, ATG5, and ATG7, inducing upregulating ULK1 and activating autophagy in RKO, HT29 autophagy-dependent cell death and exerting strong and specific and HCT116 human CRC cells (48). In addition, lncRNA small tumor-suppressive efficacy (40)(Figure 2B). In addition, LL-37, nucleolar RNA host gene 14 (SNHG14) is often highly expressed an antimicrobial peptide, is closely related to cellular processes in a variety of cancers, leading to poor progression; in CRC, such as apoptosis and autophagy, inhibiting the carcinogenesis SNHG14 suppresses miR-186 to upregulate ATG14, inducing of intestinal cells. However, due to the complex pathogenesis of autophagy in SW620 and SW480 human CRC cells (49). Cancer CRC, whether LL-37 can treat CRC by regulating autophagy still susceptibility candidate 9 (CASC9) is a lncRNA highly expressed need to explore (41). in CRC in both TCGA and The Encyclopedia of RNA Interactomes (ENCORI) datasets, which high expression is associated with poor patient prognosis. Inhibition of CASC9 Noncoding RNAs targeting autophagy upregulates the phosphorylation level of AMPK and suppresses Akt-mTOR signaling, inhibiting tumor growth and inducing In recent years, ncRNA has been found to play critical roles autophagy in HCT116 and SW480 human CRC cells, which is a promising strategy for CRC therapy (50). Moreover, lncRNA in various cellular physiological processes and is closely related Frontiers in Oncology 05 frontiersin.org Qiang et al. 10.3389/fonc.2022.1007509 A B FIGURE 2 Therapeutic strategies targeting autophagy for CRC therapy. (A–C) Small-molecule compounds, polypeptide, and ncRNAs for targeting autophagy in CRC therapy. Various small-molecule compounds, the polypeptide, and multiple ncRNAs modulate critical regulators of autophagy to treat CRC. (D) Photodynamic therapy targeting autophagy in CRC therapy. Multiple photosensitizers with specific wavelength light source irradiation induce autophagy-associated cell death, participating in CRC therapy. (E) Adjuvant chemotherapy by autophagy for CRC therapy. Autophagy inhibitors can effectively suppress the cytoprotective autophagy triggered by long-term chemotherapy and restore the sensitivity of tumors to chemotherapy drugs, enhancing the effectiveness of chemotherapy. functional intergenic repeating RNA element (FIRRE) is often downstream Bcl-2 to suppress beclin1 to inhibit autophagy in located in the nucleus and can bind PTBP1 to promote its vitro and in vivo (53)(Figure 2C). Although the application of translocation to the cytoplasm to stabilize the cytoplasmic ncRNAs in tumor diagnosis and treatment is still in the early mRNA BECN1, increasing the level of autophagy in RKO stage, as more and more mechanisms are discovered, we believe human CRC cells (51)(Figure 2C). that the clinical application of ncRNAs is just around the corner. Importantly, circular RNAs (circRNAs) are a special class of ncRNAs that often function as competing endogenous RNAs (ceRNAs) for miRNAs, which implied an emerging strategy in Photodynamic therapy targeting cancer therapy. For instance, circCUL2 acts as a sponge for miR- autophagy 208a-3p to inhibit tumor proliferation via upregulating protein phosphatase 6 catalytic subunit (PPP6C), which induces Photodynamic therapy (PDT), an emerging minimally autophagy in SW480 and SW620 human CRC cells and the invasive procedure for cancer therapy, relies on specific SW480 xenograft model (52). Similarly, circHIPK3 acts as a wavelength light source irradiation to activate photosensitizers sponge for miR-637 to upregulate STAT3, activating in tumors to generate biotoxic singlet oxygen and other highly Frontiers in Oncology 06 frontiersin.org Qiang et al. 10.3389/fonc.2022.1007509 reactive oxygen species (ROS), which in turn oxidatively xenografts (60). In addition, knockdown of ATG7 resensitizes damages tumors, and exerts therapeutic effects by inducing SW480 and HT29 human CRC cells to Irinotecan and 5-FU, various forms of cell death such as apoptosis or autophagy overcoming chemoresistance, again confirming the feasibility of (54, 55). Compared with traditional treatment strategies for autophagy inhibitors to alleviate chemoresistance (31). Similarly, cancer, PDT is less invasive, has better selectivity and a inhibition of autophagy also increases radiosensitivity, which broader range of applications, and can be repeated multiple implies a potential CRC therapeutic strategy. For instance, times without drug resistance or toxicity (55). Currently, PDT to downregulation of long non-coding RNA homeobox transcript induce autophagy has achieved a series of progress in CRC antisense intergenic RNA (HOTAIR) upregulates miR-93 to therapy. For instance, treatment of HCT116 and SW480 human downregulate ATG12, improving the effect of radiotherapy via CRC cells with the second-generation photosensitizers meta- inhibiting autophagy in SW480 and HCT116 human CRC cells tetrahydroxyphenylchlorin (m-THPC) and verteporfin(VP) and CRC xenograft models (61)(Figure 2E). produces a large amount of ROS, induces autophagy by activating c-Jun N-terminal kinase (JNK) and inhibiting the phosphorylation of mTOR; in addition, m-THPC and VP also Conclusions and perspectives effectively suppress the tumor progression of HCT116 xenografts (56). Importantly, both high-speed and short-term CRC is a common malignant tumor with a high global acute PDT (aPDT) and low-speed and long-term metronomic incidence and mortality rate, and its therapeutic strategies have PDT (mPDT) with the photosensitizer 5-aminolevulinic acid been mainly dependent on surgery, radiotherapy, and (ALA) can induce autophagy in SW837 human CRC cells, and chemotherapy so far. Unfortunately, some patients are already ALA-mPDT induces autophagy earlier and exhibits stronger at an advanced stage of CRC when they are detected and cannot antitumor effect than ALA-aPDT (57). Similarly, PDT with the be treated surgically. Therefore, development of some new photosensitizer zinc phthalocyanine (ZnPc) at a light flux of 12 emerging therapeutic approaches should be urgent. On one 2 2 J/cm or 24 J/cm induces autophagy in SW480 human CRC hand, autophagy removes damaged nucleic acids and cellular cells (58)(Figure 2D). organelles to protect cells from stress damage, effectively reducing the probability of CRC occurrence. On the other hand, autophagy may help CRC respond to the therapeutic Adjuvant chemotherapy targeting stimuli, provides the energy required for tumor proliferation autophagy through catabolism, and even resists drug stimuli to resistance. Notably, the crucial pathway for autophagy regulation is one 5-FU is the first drug recognized as an effective chemotherapy of the current research hotspots in CRC pathology. Many drug for CRC, which has been widely used in CRC clinical therapy canonical regulators of autophagy processes (e.g., ULK1, since 1957. Unfortunately, long-term treatment inevitably develops ATG5, ATG16L1) are aberrantly expressed in CRC patients. chemoresistance, resulting in tumor relapse; notably, autophagy In addition, some studies knocked down or overexpressed plays a critical role in its drug resistance mechanism. Once 5-FU critical regulators in each stage of autophagy to rationally gives tumors stress, autophagy can provide additional nutrients to utilize its two sides, initially showing favorable antitumor meet the metabolic needs of tumors, resulting in abnormal effects. In short, an in-depth exploration of crucial pathways proliferation and weakening the effectiveness of chemotherapy for autophagy regulation in CRC and the corresponding effective (6). Therefore, the therapeutic strategy of 5-FU combined with interventions will considerably improve CRC therapy. autophagy inhibition may considerably improve the survival rate Currently, several small-molecule compounds targeting of CRC patients. For instance, the treatment of 5-FU decreases the autophagy (e.g., Fangchinoline, Chaetocochin J, and Celastrol) expression of serine hydroxymethyltransferase-2 (SHMT2), which have been achieving some promising preclinical results and promotes autophagy and triggers 5-FU resistance, resulting in poor exerted a great potential on potential CRC therapies. Notably, prognosis of CRC patients; while 5-FU combined with the compared with small-molecule compounds, polypeptides [e.g., autophagy inhibitor chloroquine (CQ) reverses the insensitivity TD-3(TFM)3(FAS)] generally have higher selectivity and to 5-FU in CRC cells with low SHMT2 expression in vitro and in stability in vivo, and are less susceptible to rejection by the vivo, thereby enhancing the effect of chemotherapy (59). immune system, exhibiting high therapeutic potential for CRC. Prodigiosin, a secondary metabolite synthesized by bacteria such In addition, some key regulatory factors (e.g., microRNA miR- as Serratia marcescens, inhibits autophagy by blocking the fusion of 338-5p, lncRNA MALAT1, and circRNA circCUL2) have also autophagosome and lysosome and suppressing the activity of been continuously identified as autophagy-related biomarkers in lysosomal hydrolase, further triggers the accumulation of LC3B- CRC, providing accumulating evidence for the availability of II and SQSTM, enhances the sensitivity of tumors to 5-FU, clinical diagnosis and treatment. As a new emerging therapeutic synergizing with 5-FU to inhibit CRC progression in HCT116 strategy, photodynamic therapy also achieved inspiring stage and SW480 human CRC cells and HCT116 cells nude mice results in CRC therapy by inducing autophagy, which provides Frontiers in Oncology 07 frontiersin.org Qiang et al. 10.3389/fonc.2022.1007509 more options for CRC patients. Interestingly, autophagy reverses Funding long-term chemotherapy-induced resistance and sensitize tumors to chemotherapeutic drugs. This work was supported by grants from the fund of the In summary, modulating autophagy has been emerging as a high-quality development of Guang ‘an People’s Hospital (Grant promising strategy for CRC therapy, which can benefit the No. 21FZ008). patients who are not suitable for traditional treatment, and can be used as adjuvant chemotherapy to overcome drug resistance. Importantly, the rapid development of new technologies, such as Conflict of interest artificial intelligence (AI) seems to be delineated the intricate dynamic balance of autophagy between CRC progression and The authors declare that the research was conducted in the treatment (62). With the continuous exploration of the absence of any commercial or financial relationships that could relationship between autophagy and CRC, we believe that the be construed as a potential conflict of interest. Janus roles of autophagy would be subtly manipulated, and more effectively therapeutic strategies will be exploited to greatly improve potential CRC therapies in the future. Publisher’s note Author contributions All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated LQ, HL participates in manuscript writing and figure organizations, or those of the publisher, the editors and the drawing; ZW, LW participates in references collection and reviewers. Any product that may be evaluated in this article, or manuscript formatting adjustments. GJ reviewed and edited claim that may be made by its manufacturer, is not guaranteed the manuscript. 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(2019) 179(5):1033–55. doi: 10.1016/j.cell.2019.10.017 doi: 10.1158/2159-8290.Cd-21-0090 Frontiers in Oncology 09 frontiersin.org Qiang et al. 10.3389/fonc.2022.1007509 Continued Glossary lncRNA long non-coding RNA MALAT1 metastasis-associated lung adenocarcinoma transcript 1 miRNAs microRNAs 5-FU 5-Fluorouracil mPDT metronomic PDT AI artificial intelligence mTOR mechanistic target of rapamycin ALA 5-aminolevulinic acid m-THPC meta-tetrahydroxyphenylchlorin AMBRA1 autophagy and beclin 1 regulator 1 ncRNA non-coding RNA AMPK AMP-activated protein kinase PDT photodynamic therapy aPDT acute PDT PDX patient-derived tumor xenograft ATG autophagy-related gene PE phosphatidylethanolamine BECN1 coiled-coil myosin-like BCL2-interacting protein PHLDA2 pleckstrin homology like domain family A member 2 BRD4 bromodomain-containing protein 4 PI3K phosphoinositide 3-kinase CASC9 cancer susceptibility candidate 9 PIK3C3 phosphatidylinositol 3-kinase catalytic subunit type 3 CDX cell-derived xenograft PIK3R4 phosphoinositide 3-kinase regulatory subunit 4 ceRNA competing endogenous RNA PPP6C protein phosphatase 6 catalytic subunit circRNA circular RNA RAB7A Ras-related protein Rab-7a CQ chloroquine RB1CC1 RB1-inducible coiled-coil 1 CRC colorectal cancer ROS reactive oxygen species ENCORI The Encyclopedia of RNA Interactomes SHMT2 serine hydroxymethyltransferase-2 ER endoplasmic reticulum SNHG6 small nucleolar RNA host gene 6 FAT4 FAT tumor suppressor homolog 4 SNHG14 small nucleolar RNA host gene 14 FDA Food and Drug Administration SNX10 sorting nexin 10 FIRRE functional intergenic repeating RNA element SOX2 sex-determining region Y-box2 HDAC histone deacetylases STAT3 signal transducer and activator of transcription 3 HOTAIR homeobox transcript antisense intergenic RNA TCGA The Cancer Genome Atlas IL-6 interleukin-6 TD tetrahedron JAK2 Janus kinase 2 TSC1/2 tuberous sclerosis complex 1 and 2 JNK c-Jun N-terminal kinase ULK1 UNC-51-like autophagy-activating kinase 1 LAMP1 lysosome-associated membrane protein 1 UVRAG UV radiation resistance-associated LIF leukemia inhibitory factor VP verteporfin ZnPc zinc phthalocyanine. 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