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AR, the cell cycle, and prostate cancer

AR, the cell cycle, and prostate cancer Review Nuclear Receptor Signaling | The Open Access Journal of the Nuclear Receptor Signaling Atlas Steven P. Balk and Karen E. Knudsen Corresponding Author: [email protected] Cancer Biology Program-Hematology Oncology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA (S.P.B.) and Department of Cell and Cancer Biology (K.E.K.), Center for Environmental Genetics (K.E.K.), and UC Barrett Cancer Center (K.E.K.), University of Cincinnati College of Medicine, Cincinnati, Ohio, USA; Karen Knudsen’s new contact information, effective December 15th, 2007, is: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson Medical College, Philadelphia, Pennsylvania, USA The androgen receptor (AR) is a critical effector of prostate cancer development and progression. The dependence of this tumor type on AR activity is exploited in treatment of disseminated prostate cancers, wherein ablation of AR function (achieved either through ligand depletion and/or the use of AR antagonists) is the first line of therapeutic intervention. These strategies are initially effective, and induce a mixed response of cell cycle arrest or apoptosis in prostate cancer cells. However, recurrent, incurable tumors ultimately arise as a result of inappropriately restored AR function. Based on these observations, it is imperative to define the mechanisms by which AR controls cancer cell proliferation. Mechanistic investigation has revealed that AR acts as a master regulator of G1-S phase progression, able to induce signals that promote G1 cyclin-dependent kinase (CDK) activity, induce phosphorylation/inactivation of the retinoblastoma tumor suppressor (RB), and thereby govern androgen-dependent proliferation. These functions appear to be independent of the recently identified TMPRSS2-ETS fusions. Once engaged, several components of the cell cycle machinery actively modulate AR activity throughout the cell cycle, thus indicating that crosstalk between the AR and cell cycle pathways likely modulate the mitogenic response to androgen. As will be discussed, discrete aberrations in this process can alter the proliferative response to androgen, and potentially subvert hormonal control of tumor progression. Received September 14th, 2007; Accepted December 7th, 2007; Published February 1st, 2008 | Abbreviations: AR: androgen receptor; ARE: androgen response element; CAK: CDK activating kinase; CDK: cyclin dependent kinase; DHT: dihydrotestosterone; ER: estrogen receptor α; G1: gap phase 1; G2: gap phase 2; HDAC: histone deacetylase; M: the phase of mitosis; PPAR: peroxisome proliferator-activated receptor; PSA: prostate specific antigen; RB: retinoblastoma tumor suppressor; S: phase of DNA replication; TR: thyroid hormone receptor; TSA: trichostatin A | Copyright © 2008, Balk and Knudsen. This is an open-access article distributed under the terms of the Creative Commons Non-Commercial Attribution License, which permits unrestricted non-commercial use distribution and reproduction in any medium, provided the original work is properly cited. Cite this article: Nuclear Receptor Signaling (2008) 6, e001 prostate cancers, and this is considered an incurable Prostate cancer is dependent on stage of the disease. Given the dependence of prostate androgen action cancer cells on the androgen signaling axis, a concerted Prostatic adenocarcinoma is the most frequently effort has been undertaken to determine the diagnosed malignancy and second leading cause of mechanism(s) by which androgens induce prostate cancer cancer death amongst men in the United States [Jemal cell proliferation and survival. et al., 2005]. Localized prostate cancer can be definitively Androgen receptor regulation in prostate cancer treated by surgical resection or through radiation therapy [Catalona et al., 1999; Denmeade and Isaacs, 2002; Dorff Androgen exerts its biological effects through the et al., 2006; Swanson, 2006]. However, invasive or even androgen receptor (AR), a member of the nuclear receptor micrometastatic disease presents a clinical challenge, as superfamily that acts as a ligand dependent transcription these tumors respond poorly to standard cytotoxic factor [Evans, 1988; Mangelsdorf et al., 1995; Shand and regimens that act through genomic insult. Therefore, Gelmann, 2006; Trapman and Brinkmann, 1996]. prostate cancers are treated based on a unique Testosterone is the most abundant androgen in the sera, characteristic, in that they are exquisitely dependent on but in prostatic epithelia is converted to a more potent androgen for development, growth, and survival [Balk, androgen, dihydrotestosterone (DHT) through the action 2002; Culig and Bartsch, 2006; Jenster, 1999; Klotz, of a resident enzyme, 5α-reductase [Russell and Wilson, 2000]. Androgen ablation triggers cell death or cell cycle 1994; Wilson, 1996]. Prior to ligand binding, the AR is arrest of prostate cancer cells [Agus et al., 1999; held inactive through association with heat shock proteins Denmeade et al., 1996; Huggins and Hodges, 1972; and is precluded from DNA binding. Ligand binding Isaacs, 1984; Knudsen et al., 1998; Kyprianou and Isaacs, releases the inhibitory heat shock proteins, and the 1988]. Thus, androgen ablation remains the primary receptor rapidly translocates to the nucleus, where it binds course of treatment for all patients with metastatic disease DNA as a homodimer on androgen responsive elements [Jenster, 1999; Klotz, 2000; Loblaw et al., 2004; Sowery (AREs) within the regulatory regions of target genes et al., 2007]. These therapies are initially effective, and [Gelmann, 2002; Marivoet et al., 1992; Trapman and result in disease remission. However, recurrent tumors Brinkmann, 1996]. Furthermore, recruitment of arise within a median of 2-3 years, wherein androgen coactivators (which contain or recruit histone acetylases) signaling has been inappropriately restored [Feldman and chromatin remodeling complexes facilitate and Feldman, 2001]. At present, few therapeutic regimens transcriptional initiation, and AR-dependent gene have been described to effectively manage recurrent www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06001 | Page 1 of 12 Review AR-cell cycle crosstalk expression ensues [Gnanapragasam et al., 2000; Heinlein Feldman and Feldman, 2001; Leewansangtong and and Chang, 2002; Heinlein and Chang, 2004]. The Soontrapa, 1999; Taplin and Balk, 2004]. First line capacity of AR to subsequently induce a gene expression treatment ablates AR function through ligand depletion, program that promotes cell cycle progression is clearly as achieved through either bilateral orchiectomy or the dependent on cell context. For example, during use of GnRH agonists. Adjuvant or second line therapies development and homeostasis it is clear that the stromal involve the use of direct AR antagonists (e.g., AR plays a major role in stimulating epithelial cell bicalutamide) which utilize at least two mechanisms of proliferation; by contrast, it is hypothesized that a action [Chodak, 2005; Klotz, 2006] . First, these agents switching mechanism arises during tumorigenesis to compete for DHT binding. Second, selected AR render the proliferative function of AR cell autonomous antagonists trigger the recruitment of transcriptional in prostate cancer cells. The specific combinations of corepressors (e.g., NCoR) to AREs, thereby fostering cofactors recruited to AREs likely also provide a active repression of AR target gene expression [Shang mechanism for tissue specific and ligand specific gene et al., 2002]. At the cellular level, androgen ablation expression. Through these actions, it is apparent that the induces cell death or cell cycle arrest, which underpins AR promotes prostate cancer survival and proliferation tumor regression [Agus et al., 1999; Denmeade et al., in prostate cancer cells [Balk, 2002; Feldman and 1996; Huggins and Hodges, 1972; Isaacs, 1984; Knudsen Feldman, 2001]. et al., 1998; Kyprianou and Isaacs, 1988]. Effective AR inhibition is also observed by a loss of detectable serum While the subsets of AR target genes that underlie each PSA. However, this remission is transient, and tumor cellular outcome have yet to be clearly defined, discovery recurrence is almost invariably observed [Balk, 2002; of at least one major AR-dependent target gene, prostate Feldman and Feldman, 2001; Leewansangtong and specific antigen (PSA) [Riegman et al., 1991], has had a Soontrapa, 1999]. Recurrence is typically preceded by a major impact on disease management. Specifically, serum rise in PSA (also called “biochemical recurrence”) PSA is monitored clinically to detect early stage disease, [Feldman and Feldman, 2001; Klotz, 2000; Trapman and track tumor burden, monitor the efficacy of therapeutic Brinkmann, 1996], and this observation yielded some of intervention, and detect the emergence of recurrent the first evidence that tumor progression is associated tumors post-therapy [Nash and Melezinek, 2000; Ryan with inappropriately restored AR function, despite et al., 2006]. Thus, readouts of AR activity are critical for sustained androgen ablation and/or the use of AR the assessment of disease progression and therapeutic antagonists. AR re-activation in recurrent tumors occurs outcome. In addition, it has been recently discovered that through multiple mechanisms, including AR amplification, chromosomal translocations occur with significant AR mutation, ligand-independent AR activation, frequency in prostate cancer which render the potentially hypersensitivity to a low ligand environment, enhanced pro-proliferative ETS genes (ERG, ETV1, or ETV4) under local production of androgens, excessive production of control of the AR-induced TMPRSS2 promoter/enhancer AR coactivators, and/or as a result of signals that disrupt [Demichelis et al., 2007; Tomlins et al., 2005; Wang et AR corepressor function [Chmelar et al., 2007; Feldman al., 2007]. However, subsequent functional investigations and Feldman, 2001; Stanbrough et al., 2006]. Indeed, it suggest that the TMPRSS2-ETS fusions may principally is now well established that such “androgen independent” exert their effects through alteration of tumor phenotypes prostate cancer remains exquisitely dependent on AR other than cell proliferation. For example, overexpression function [Chen et al., 2004; Cheng et al., 2006; Yuan et of ETV1 in normal or transformed prostatic epithelia had al., 2006]. Since AR appears to be a key determinant of no impact on cellular proliferation rates or cell cycle prostate cancer growth and progression, it is imperative progression, but facilitated invasion of these models to dissect the mechanisms by which AR governs cellular [Tomlins et al., 2007]. Thus, the contribution of these proliferation in prostate cancer cells. fusions to alterations in cell cycle control has yet to be well resolved. Lastly, it is possible that non-genomic AR Mitogenic signaling and the cell cycle signaling may influence the proliferative program. It is machinery: an overview known that androgen stimulation in AR-positive cells can trigger rapid activation of the MAPK pathway, and thereby Transitions into and within the mitotic cell cycle are potentially induce a mitogenic response. Consistent with dictated by the coordinate activation of cyclin-dependent kinase (CDK)/cyclin complexes, wherein cyclin binding this idea, rapid androgen signaling was recently identified induces the catalytic activity of the kinase [Lee and as a major stimulus for meiotic progression in Xenopus oocytes, and has also been linked to muscle cell Sicinski, 2006; Malumbres and Barbacid, 2007; Sherr, proliferation [White et al., 2005; Yoshioka et al., 2006]. 1996; Sherr and Roberts, 2004]. Mitogenic signaling pathways generally induce cell cycle progression through Thus, while the mechanisms underpinning the capacity ordered activation of CDK-cyclin complexes, whereas of AR to induce a mitogenic program may be diverse and dependent on cell context, it is clear that ligand-dependent anti-mitogenic signals that result from extracellular events activation of AR is a limiting factor for engagement of the (e.g., nutrient depletion) or intracellular insults (e.g., DNA damage) typically serve to attenuate CDK function. cell cycle machinery in prostate cancer cells. Although the signals that dictate commitment to the cell Given these functions, inhibition of AR activity is the major cycle are often cell type-specific, the core machinery that therapeutic goal for management of metastatic disease, drives the cell cycle engine is well conserved. Prior to as achieved via multiple mechanisms [Balk, 2002; mitogenic stimulation cells can exit the cell cycle and www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06001 | Page 2 of 12 Review AR-cell cycle crosstalk enter into a resting stage deemed “G ”. At this stage, histone gene expression. Recent findings demonstrate several key gatekeepers of cell cycle transitions are that these activities are associated with both catalytic invoked to prevent unscheduled cell cycle progression. (CDK2 kinase dependent) and non-catalytic functions Paramount amongst these is activation of the [Geng et al., 2007; Lee and Sicinski, 2006]. Subsequently, retinoblastoma tumor suppressor protein (RB), which transition through the remainder of the cell cycle (G2 and assembles transcriptional repressor complexes on the M phase) is driven by ordered activation of CDK1-cyclin promoters of target genes that are required to initiate A and CDK1-cyclin B complexes [Shapiro, 2006]. Cyclin DNA replication (e.g., cyclin A, PCNA) [Knudsen and B production steadily rises in G2; once reaching a Knudsen, 2006]. Many such critical RB target genes are threshold level, mitotic entry ensues dependent on this primed for activation by residence of activator E2F/DP1 kinase. CDK1-cyclin B activity continues to increase complexes on the promoter regions, but the transcriptional throughout early mitosis until anaphase, wherein rapid repressor complexes recruited by RB (which include degradation of cyclin B (and thereby loss of CDK1 activity) histone deacetylases, SWI/SNF chromatin remodeling triggers mitotic exit and completion of the cell cycle [Pines, complexes and/or polycomb group proteins) act as potent 2006; Shapiro, 2006]. inhibitors of transcriptional activation [Johnson and To counterbalance this sophisticated coordination of Degregori, 2006]. Thus, mitogenic stimuli must act to CDK-cyclin activation, mechanisms exist to halt the cell balance RB function, and do so through activation of cycle in the presence of cellular insult. RB typically CDK-cyclin complexes. remains hyperphosphorylated/inactivated until mitotic Mitogenic stimuli typically trigger accumulation of D-type exit, when the “braking” action of the RB tumor suppressor cyclins (cyclins D1, D2, and/or D3), which can bind and is reset by phosphatase activity. However, many activate the early G1 kinases CDK4 or CDK6 [Lee and anti-proliferative signals result in RB Sicinski, 2006; Sherr and Roberts, 2004]. D-cyclin dephosphorylation/activation, thus inducing RB-dependent production is a tightly regulated process, which has been cessation of cell cycle progression. For example, DNA Cip1 most extensively studied with cyclin D1 [Alao, 2007; damage signals that induce p53-mediated p21 Gladden and Diehl, 2005; Knudsen, 2006]. The cyclin D1 induction to high levels can cause downregulation of transcript is controlled at the level of mRNA production, CDK2 activity and thereby prevent RB phosphorylation stability, splicing, and translation. Once produced, cyclin [Sherr and Roberts, 2004]. Alternatively, the related CDK2 Kip1 D1 action is subjected to further regulation at the level of inhibitor p27 is often induced by signals such as serum subcellular localization, targeted degradation, and CDK4/6 deprivation, thus acting through similar pathways to halt binding [Alt et al., 2000; Gladden et al., 2006]. These cell cycle progression [Nickeleit et al., 2007]. From these Cip1 latter processes appear to involve p21 , which was observations, it is apparent that the G1-S cell cycle originally classified as a CDK inhibitor. This classification machinery plays critical roles in the response to the intra- Cip1 may be overly simplistic, as while p21 can inhibit CDK2 and extracellular environments. While these general Cip1 complexes, p21 is conversely important for promoting principles are conserved in the majority of cell types, it is formation, activation and nuclear enrichment of increasingly apparent that different mitogenic cues utilize CDK4/6-cyclin D complexes [Alt et al., 2002; Cheng et disparate mechanisms to engage the cell cycle al., 1999; LaBaer et al., 1997; Sherr and Roberts, 1999]. machinery. Once active, the principal cell cycle function of CDK4/6-cyclin D complexes is to initiate RB AR governs the cyclin D-RB axis in phosphorylation. The concept that this is the major cell prostate cancer cells cycle function of CDK4/6 is supported by the observation Analyses of AR-dependent cell cycle progression in that RB-deficient tumor cells are resistant to cell cycle prostate cancer cells have shown that androgen is a arrest induced by inhibition of the kinase [Lukas et al., critical regulator of the G1-S transition (Figure 1). Prostate 1995]. Thus, loss of RB in cancer is proposed to bypass cancer cells deprived of androgen arrest in early G1 the requirement for this early event in cell cycle phase, concomitant with loss of cyclin D1 and cyclin D3 progression. expression, attenuated CDK4 activity (expression Although RB phosphorylation/inactivation is initiated by unchanged), and hypophosphorylated/activated CDK4/6, this only partially compromises the RB retinoblastoma tumor suppressor [Knudsen et al., 1998; Xu et al., 2006]. Recent studies revealed that androgen transcriptional repressor function [Knudsen and Knudsen, induces D-type cyclin expression via mTOR-dependent 2006]. Subsequent to this event, a downstream kinase (CDK2) is responsible for completing RB phosphorylation enhancement of translation [Xu et al., 2006]. The ability and thereby extinguishing its repressor function. Critically, of androgen to modulate cyclin D translation is distinct from mechanisms utilized by other hormones. For the requisite cyclins associated with CDK2, cyclins E and example, estrogen induces cyclin D1 transcription in A, are themselves regulated via RB-mediated transcriptional repression. Thus, CDK2-cyclin complexes breast cancer cells, through the ability of its cognate constitute a feed-forward mechanism to stimulate cell receptor (the estrogen receptor, ER) to directly modulate cyclin D1 regulatory regions [Eeckhoute et al., 2006; cycle progression through modulation of RB. In addition, Sabbah et al., 1999]. Thus, androgen regulation of early cyclin E- and cyclin A-assembled complexes impinge on additional substrates that promote activation of the DNA G1 events is specific to this class of hormone. replication machinery, centrosome duplication, and www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06001 | Page 3 of 12 Review AR-cell cycle crosstalk Figure 1. AR-cell cycle crosstalk. Activated AR stimulates the accumulation of cyclin D1 (D1), through mammalian Target of Rapamycin (mTOR), Cip1 to activate CDK4 and promote phosphorylation of the retinoblastoma (RB) tumor suppressor. In addition, AR-induced expression of p21 and Kip1 degradation of p27 further enhance cycD1/CDK4 and cycE/CDK2-dependent inactivation of RB and allow expression of E2F target genes like cyclin A (CycA). Cyclin A in turn activates CDK2 to drive G1-S phase transition. Subsequently engaged components of the cell cycle machinery then impinge on AR to regulate the androgen response. Elevated cyclin D1 acts as in a negative feedback loop to attenuate AR activity, thereby modulating androgen action. In G2-phase, CDK1 promotes the phosphorylation and activation of AR. However, AR is degraded in M-phase and is purposed to be a “licensing factor” for DNA replication. Components that suppress AR function are outlined in red, whereas positive effectors of AR activity are outlined in green. Cip1 In contrast to the D-type cyclins, cyclin E levels remain examination of p21 in prostate cancer has revealed relatively unchanged by androgen withdrawal, indicating that expression is enhanced in tumors, and correlates that alteration of cyclin E expression is not a major with a higher proliferative index and Gleason grade mechanism of androgen action [Knudsen et al., 1998; Xu [Aaltomaa et al., 1999; Baretton et al., 1999]. et al., 2006]. However, cyclin A levels and overall CDK2 To date, these observations culminate in a model wherein activity are diminished upon androgen ablation. These androgen induces cyclin D1 accumulation through mTOR, data are consistent with the observation that androgen promotes active CDK4/cyclin D1 assembly (potentially depletion invokes RB activity, as cyclin A is a Cip1 through p21 induction), and facilitates CDK2 activation well-established target of RB-mediated transcriptional Kip1 through degradation of p27 . These collective events repression. Furthermore, androgen depletion induces Kip1 result in RB phosphorylation, de-repression of cyclin A p27 , which likely contributes to the observed reductions expression, and S-phase progression. Based on this in CDK2 activity [Knudsen et al., 1998]. This supposition knowledge of AR function, it could be hypothesized that is consistent with more recent findings which Kip1 aberrations in the cyclin D-RB axis in cancer could demonstrated that low p27 expression is predictive for supplant the requirement for androgen and contribute to shorter time to disease recurrence in prostate cancer Kip1 disease progression. Investigations challenging this [Halvorsen et al., 2003]. Similarly, p27 loss in the hypothesis have revealed a significant function for RB in context of a PTEN mutation promotes a tumorigenic controlling the response to androgen ablation therapy, phenotype in the prostate [Gao et al., 2004]. Interestingly, Kip1 and unique crosstalk mechanisms between the AR and upon re-stimulation with androgen, p27 is degraded Cip1 cell cycle pathways that assist in coordinating and/or [Ye et al., 1999]. By contrast, p21 expression is lost maintaining androgen-dependent cellular proliferation. upon androgen ablation in prostate cancer cells in vitro, which correlates with a higher proliferative index in human RB function in prostate cancer and the tumor specimens [Knudsen et al., 1998; Kolar et al., Cip1 2000]. Thus, p21 correlates with androgen stimulation response to AR-directed therapeutics and mitogenic proliferation in prostate cancer. As discussed above, CDK-mediated RB Cip1 Remarkably, p21 has been validated as a direct AR phosphorylation/inactivation is a key component of the target gene [Lu et al., 1999], and its induction upon proliferative response to AR. These findings suggest that androgen stimulation may assist in assembling active RB loss may play an influential role in prostate cancer CDK4/cyclin D1 complexes. In agreement with this, www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06001 | Page 4 of 12 Review AR-cell cycle crosstalk development and/or the response to AR-directed the ability of AR to control the G1-S transition is likely a therapeutics. Consistent with this concept, RB is lost or critical component for maintaining androgen dependence. inactivated in approximately 30-60% of prostatic While these studies highlight the importance of AR in adenocarcinomas through disparate mechanisms [Brooks governing the cell cycle machinery, it is becoming et al., 1995; Ittmann and Wieczorek, 1996; Jarrard et al., increasingly apparent that substantive crosstalk between 2002; Tricoli et al., 1996]. Accordingly, several model the AR and cell cycle pathways may also contribute to systems have been developed to more directly probe the this process. importance of RB function in this tissue. Transgenic mouse models wherein RB and p53 are inactivated by Cell cycle regulation of AR SV40 large T- and small T-antigen overexpression in the Only a small number of studies have directly examined luminal epithelia result in high grade PIN and/or prostate the influence of cell cycle on AR activity. Nonetheless, cancer (often with neuroendocrine phenotypes) and can many of the proteins found to interact with or modulate achieve androgen independence after castration [Gingrich AR are also regulated during the cell cycle. These include et al., 1997; Greenberg et al., 1995]. Tissue recombination proteins whose expression or activity are increased in G studies showed that RB-deficient prostatic epithelia give (RB), G1 to S phase (cyclin D1, cyclin E, Cdk6), or G2 rise to hyperplastic disease in 40% of grafted samples (Cdk1). Therefore, it appears likely that AR activity is when recombined with wild-type rat urogenital modulated during the cell cycle through interactions with mesenchyme [Wang et al., 2000]. Similarly, conditional one or more of these proteins. Moreover, AR may be RB deletion in the prostate resulted in focal hyperplasia further modulated directly during the cell cycle by that is potentially reminiscent of early stage disease transcriptional or post-transcriptional mechanisms, the [Maddison et al., 2004b]. These effects are exacerbated latter including alterations in phosphorylation, acetylation, by combinatorial p53 deletion, which results in rapidly or ubiquitination that affect transcriptional activity or progressing metastatic carcinomas of the prostate [Zhou stability. The sections below first outline reported et al., 2006]. Together, these data are indicative that interactions between AR and cell cycle regulated proteins, inactivation of RB may prime prostate cells to become and then describe studies that have directly examined cancerous when subjected to other insults. AR during the cell cycle. In addition to these observations, emerging evidence Retinoblastoma protein (RB) suggests that RB inactivation may also subvert or weaken Direct interactions between AR and RB have been the requirement for AR-mediated cell cycle progression. reported by two groups based on GST-RB and Although studies are few in number, one study showed mammalian two-hybrid protein interaction approaches that RB mRNA expression was low in 36% of patients that failed combined androgen blockade [Mack et al., [Lu and Danielsen, 1998; Yeh et al., 1998]. The interacting site on the AR was mapped to the AR N-terminal domain. 1998]. Furthermore, by FISH analysis it was reported that Overexpression of RB enhanced AR transcriptional RB loss is almost four times more frequent after hormone activity, while AR transcriptional activity was lost in cells therapy [Kaltz-Wittmer et al., 2000]. Since these data indicate that RB inactivation and/or deletion may facilitate that were RB-negative and was decreased in cells expressing RB-binding oncogenes. Interestingly, RB has the transition to androgen independence, a recent study also been reported to interact with the GR, and RB challenged this hypothesis in vitro, through overexpression can similarly enhance GR transcriptional shRNA-mediated depletion of RB in AR-dependent prostate cancer cells [Sharma et al., 2007]. In these activity [Singh et al., 1995]. However, in contrast to AR, the GR remains transcriptionally active in RB deficient models, RB depletion did not confer a proliferative cells [Lu and Danielsen, 1998]. Significantly, the GR advantage in the presence of androgen; rather coactivation by RB is dependent on Brm, with RB and RB-deficient cells failed to elicit a cytostatic response (as compared to RB-positive isogenic controls) when Brm forming a complex and both being required for GR coactivation [Singh et al., 1995]. It is not clear whether a challenged with androgen ablation, AR antagonists, or similar mechanism mediates RB coactivation of AR. combined androgen blockade. Not yet considered, however, is whether loss of RB or deregulation of G1-S AR has also been found to interact directly with an alleviates the need for unliganded AR, and this RB-associated protein, retinoblastoma-associated Kruppel determination is the focus of ongoing projects. However, protein (RbaK) [Hofman et al., 2003]. RbaK contains a studies examining the impact RB loss were subsequently Kruppel-associated box (KRAB) repressor motif at its extended to determine the impact of RB loss on the N-terminus, in conjunction with multiple Kruppel type zinc response to second line chemotherapeutic intervention, finger domains, and contributes to the RB-dependent as reports in other cell systems have suggested that loss regulation of E2F transcription factors. RbaK interacts of RB-dependent DNA damage checkpoints can sensitize directly with RB and appears to interact independently cells to cytotoxic agents [Harrington et al., 1998; Knudsen with the AR LBD based on mammalian-two hybrid and et al., 1998]. Indeed, RB-depleted prostate cancer cells coimmunoprecipitation experiments, with the interaction demonstrated enhanced susceptibility to cell death being androgen-independent. Although RbaK contains induced by a select subset of chemotherapeutic agents. the KRAB repressor motif, overexpression enhances AR Combined, these data indicate that RB status may be an transcriptional activity by unclear mechanisms. Further important determinant of the response to AR-directed studies are needed to determine precisely how RB and therapeutic strategies against prostate cancer, and that www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06001 | Page 5 of 12 Review AR-cell cycle crosstalk RbaK modulate AR activity, and to determine the AR activity and androgen-dependent proliferation in biological significance of these interactions for AR activity, AR-positive prostate cancer cells [Petre-Draviam et al., particularly in RB negative PCa [Sharma et al., 2007]. 2003]. As expected, AR-negative prostate cancer cells are refractory to the repressor function of cyclin D1 [Burd D-cyclins et al., 2006]. These data are consistent with observations that AR activity is highly regulated as a function of the Although androgen stimulates cyclin D1 accumulation cell cycle, wherein cyclin D1 levels inversely correlate and concomitant CDK4 activation [Knudsen et al., 1998; with AR activity [Martinez and Danielsen, 2002]. Xu et al., 2006], restoration of cyclin D1 expression under Moreover, in a mouse model of prostate cancer, cyclin conditions of androgen ablation is insufficient to drive D1 levels decrease as a function of progression, whereas androgen-independent proliferation [Fribourg et al., 2000]. cyclin E levels are elevated; this observation led to the Moreover, it was observed that modest elevations of hypothesis of a putative “cyclin switch” that may occur in cyclin D1 in the presence of androgen inhibit (rather than prostate cancer progression [Maddison et al., 2004a] , enhance) cellular proliferation [Burd et al., 2005; although this concept has yet to be validated in human Petre-Draviam et al., 2003]. This unexpected capacity of specimens. Based on these collective observations, it is cyclin D1 to attenuate cell cycle progression is specific hypothesized that cyclin D1 serves as a “negative to AR-positive prostate cancer cells, thus suggesting a feedback switch” to modulate androgen-dependent gene putative relationship between cyclin D1 and AR function. expression and concomitant cellular proliferation, thereby Detailed examination of this interaction revealed an governing the strength and duration of the androgen unexpected and unique role of cyclin D1 in control of AR response. Recent analyses indicated that these activity. “balancing” functions of cyclin D1 are disrupted in prostate cancer [Burd et al., 2006; Comstock et al., 2007; In addition to its ability to modulate CDK4 kinase activity, Knudsen, 2006]. In the context of normal prostatic increasing evidence has demonstrated that cyclin D1 epithelia, the role of AR is to suppress cell proliferation harbors CDK-independent functions in controlling transcription factor action [Coqueret, 2002]. Cyclin D1 and drive differentiation. While not yet examined, it is possible that cyclin D1 may be important for suppressing can directly interact with and modulate a large number these functions to allow for entry into the cell cycle. of transcription factors, including v-Myb, DMP1, Sp-1, and MyoD. A landmark paper demonstrated the relevance Cdk6 of cyclin D1-mediated transcriptional regulation, wherein it was shown that the ability of cyclin D1 to interact with One study found that AR could be coactivated by and modulate the CCAAT/enhancer binding protein (and transfected Cdk6 [Lim et al., 2005]. Importantly, this repress a large subset of genes) has a major coactivation was not due to sequestration of cyclin D1, consequence in human tumors [Lamb et al., 2003]. In as it was observed in cyclin D1-deficient NIH3T3 cells. addition, it has been recently shown that “kinase Moreover, coactivation was not prevented by a mutation independent” functions of cyclin D1 underlie mammary in Cdk6 that prevents cyclin D1 binding, or by point gland development, in that in vivo knock-in of cyclin D1 mutations that prevent binding of p16INK4a or inhibit mutants that are unable to activate CDK4 can effectively catalytic activity. Cdk6 was further shown to bind AR reverse the mammary gland phenotype observed in cyclin based on coimmunoprecipitation of transfected AR and -/- D1 mice [Landis et al., 2006]. Thus, the Cdk6, and this interaction was similarly not blocked by CDK4-independent functions of cyclin D1 appear to serve the above mutations that prevent cyclin D1 and p16INK4a critical cellular functions. binding, or catalytic activity. Stable transfection of Cdk6 into LNCaP cells could enhance androgen stimulated The largest class of transcription factors known to be growth and expression of the androgen regulated PSA modulated by cyclin D belong to the nuclear receptor gene. Finally, ChIP experiments indicated that Cdk6 was superfamily, including ER (estrogen receptor α), TR part of the AR transcriptional complex that assembles on (thyroid hormone receptor), PPARγ and AR [Coqueret, the PSA gene. Further studies are clearly needed to 2002; Ewen and Lamb, 2004]. In the case of AR, cyclin determine the molecular basis for this kinase independent D1 binds directly to the N-terminus of the receptor and AR coactivation by Cdk6. Interestingly, Cdk6 expression blocks conformational changes that are required for in androgen-sensitive prostate cancer cells increases in maximal AR activity upon ligand activation (N-C response to androgen as cells move from G1 to S phase, interaction) [Burd et al., 2005; Petre-Draviam et al., 2005]. which may then provide a positive feedback loop to further Moreover, cyclin D1 associates with histone deacetylase enhance AR activity [Bai et al., 2005]. 3 (HDAC3), and recruitment of HDAC activity is essential for its corepressor functions [Lin et al., 2002; Cyclin E Petre-Draviam et al., 2005]. These actions of cyclin D1 Cotransfection studies carried out with AR, ARE-CAT are independent of CDK activity, and a repressor domain reporter, and cyclin D1, E, and A showed that cyclin E within the protein (encoded by amino acids 142-253) has could specifically enhance androgen-stimulated been identified which is capable of supporting both cyclin transcriptional activity [Yamamoto et al., 2000]. This D1 corepressor functions [Petre-Draviam et al., 2005]. coactivation was not dependent on cyclin E binding to The biological consequence was shown in that even Cdk2, was independent of cell cycle progression, and modest induction of cyclin D1 levels (at stoichiometric was not observed for GR or PR. Cyclin E transfection into levels with the receptor) are sufficient to suppress both www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06001 | Page 6 of 12 Review AR-cell cycle crosstalk LNCaP cells similarly enhanced expression of the Cdk1 endogenous PSA gene. An interaction between AR and Cdk1 is activated in the G2 phase of the cell cycle and is cyclin E was demonstrated by mammalian two-hybrid the critical Cdk required for mitosis. As noted above, Cdk1 protein interaction assays and by coimmunoprecipitation associates with cyclin B and is then activated by removal of transfected proteins. The interaction was mapped to of inhibitory phosphates (mediated by Cdc25 isoforms) the AR N-terminal domain, and GST pulldowns indicated and by an activating T loop phosphorylation mediated by that cyclin E was interacting with a domain at the Cdk7. The unliganded AR is phosphorylated primarily at C-terminal end of the AR N-terminal domain (amino acids one serine-proline site in the N-terminal domain (Ser-94), 419-556). As above, further studies are needed to and is phosphorylated at multiple additional Ser-Pro sites determine how cyclin E mediates AR coactivation and in response to androgen [Gioeli et al., 2002; Kuiper and whether this interaction may contribute to PCa Brinkmann, 1995; Zhou et al., 1995]. These are candidate development or progression. sites for Cdk1 and other proline-directed kinases, and studies using Cdk1 transfection and Cdk inhibitors CDK-activating kinase (CAK)/Cdk7 indicate that Cdk1 phosphorylates at least one site in the CDK-activating kinase (CAK), composed of Cdk7, cyclin AR N-terminus (Ser-81) [Chen et al., 2006]. Significantly, H, and MAT1, mediates the phosphorylations of both transfection of cells with activated Cdk1 was found to Cdk2 and Cdk1 that are required for full activation and enhance the stability and transcriptional activity of AR. cell cycle progression. CAK is also a component of the Conversely, Cdk1 inhibitors decreased AR expression transcriptional machinery, and can mediate and transcriptional activity, although these drugs are not phosphorylation of ER and RAR [Rochette-Egly et al., highly specific for Cdk1 and may also effect AR by 1997; Trowbridge et al., 1997]. Immunoblotting of anti-AR targeting other Cdks such as Cdk7 [Chen et al., 2006]. immunoprecipitates identified the TFIIH transcription Although Cdk1 phosphorylates AR, site directed factor complex, which contains CAK, and further mutagenesis of Ser-81 and of additional Ser-Pro did not experiments demonstrated an interaction between AR block the ability of Cdk1 to stabilize AR, indicating that and CAK [Lee et al., 2000]. Transfection of the individual multiple sites may mediate this effect or that Cdk1 CAK proteins could weakly enhance AR transcriptional stabilizes AR by an indirect mechanism. activity, with greater coactivation when all three components were cotransfected. Coprecipitation Interestingly, an analysis of PCa clinical samples from experiments in vitro with S-labeled CAK proteins patients who had relapsed after androgen deprivation indicated that Cdk7 and cyclin H could interact with the therapy showed that cyclin B1, cyclin B2, and Cdk1 were AR N-terminal domain. These studies support the the most highly overexpressed cell cycle regulatory genes conclusion that TFIIH, as a general transcription factor, relative to primary untreated tumors [Stanbrough et al., interacts with AR. However, further studies are needed 2006]. As noted above, both Cdc25B and Cdc25C were to determine whether CAK phosphorylates AR or also found to be increased in higher grade prostate cancer selectively enhances its activity, or whether it directly and in tumors that relapsed after androgen deprivation modulates AR during the cell cycle. therapy [Ngan et al., 2003; Ozen and Ittmann, 2005]. Cyclin B expression also increases with disease Cdc25B progression in the murine TRAMP model of prostate cancer [Maddison et al., 2004a]. Taken together, these The Cdc25 dual function phosphatases (Cdc25A, B, and observations suggest that Cdk1 may contribute to AR C) mediate the activation of Cdk1 by removal of inhibitory activation in advanced cancers. In support of this phosphates from Thr-14 and Tyr-15. The exact functions hypothesis, the AR activation mediated by low levels of of each Cdc25 isoform are not yet clear, but recent data DHT in C4-2 cells (a subline of LNCaP cells that is indicate that Cdc25B specifically dephosphorylates and hypersensitive to low androgen levels) could be blocked activates cyclin B-Cdk1 complexes on centrosomes by treatment with a Cdk inhibitor [Chen et al., 2006]. [Lindqvist et al., 2005]. Significantly, Cdc25B has also been identified as a steroid receptor coactivator that can Direct assessment of transcriptional AR enhance the activity of ER, PR, GR, and AR [Ma et al., 2001; Ngan et al., 2003]. Cdc25B can interact directly activity during the cell cycle with these steroid receptors and stimulate their activity One study has directly examined modulation of AR in a cell-free transcription system. Surprisingly, this transcriptional activity during the cell cycle [Martinez and stimulation is not dependent on Cdc25B phosphatase Danielsen, 2002]. In this study, AR transcriptional activity activity, and its molecular basis remains unclear. in L929 cells (which express an endogenous AR) was Interestingly, both Cdc25B and Cdc25C were increased examined using integrated ARE regulated reporter genes in higher grade prostate cancer, with Cdc25C and a novel (MMTV-CAT and probasin-CAT). This study found that activated splice variant being further increased in PCa AR transcriptional activity (but not GR activity) was that relapses after androgen deprivation therapy [Ngan markedly decreased at the G1/S transition, and was et al., 2003; Ozen and Ittmann, 2005]. The interaction regained during S-phase. AR protein level was also with AR suggests that Cdc25B may contribute to PCa reduced at the G1/S transition, but this decrease was not progression both through effects on AR activation and as marked as the loss of transcriptional activity. A possible cell cycle. mechanism for the decreased AR expression during G1/S is increased E2F1, which has been found to suppress www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06001 | Page 7 of 12 Review AR-cell cycle crosstalk AR gene expression through binding to the AR promoter activities towards AR are not known to be cell [Davis et al., 2006]. cycle-regulated. Interestingly, Cdk1 has been reported to stabilize AR protein, although it is not clear whether Significantly, an HDAC inhibitor (TSA) could partially this is due to direct AR phosphorylation or other indirect restore AR transcriptional activity at the G1/S transition mechanisms [Chen et al., 2006]. Therefore, the decline without increasing AR protein levels. One interpretation in Cdk1 activity that occurs at the end of mitosis may of this result is that AR recruitment of coactivator proteins contribute to the marked increase in AR degradation that with HAT activity becomes limiting at the G1/S transition, is observed in early G1. resulting in decreased histone or AR acetylation. However, while histone acetylation can enhance Conclusions transcription, the role of AR acetylation in regulating AR The clinical challenges in prostate cancer center on activity is not clear [Popov et al., 2007]. Moreover, more controlling the action of the AR, which is required for both recent data show that HDAC inhibitors decrease AR tumor development and disease progression. Selective expression through inhibition of Hsp90, which must be pressure brought on by androgen ablation typically results deacetylated by HDAC6 for activity [Kovacs et al., 2005]. in a bypass mechanism to activate the receptor in the In any case, the multiple functions of HDACs make it absence of ligand, and thereby restore AR-dependent difficult to clearly assess their roles in regulating AR cellular proliferation. Thus, dissecting the mechanisms activity during cell cycle. by which AR governs cell cycle progression is instrumental for the design of new strategies to treat One possible mediator of this loss of AR transcriptional recurrent disease. It is apparent that activated AR governs activity at the G1/S transition is clearly cyclin D1, which the G1-S progression, and emerging evidence indicates increases during G1 to S progression and can function that cross talk between AR and the downstream cell cycle as a potent AR corepressor (see above). A second machinery serves a critical role in modulating the possible mediator is RB, which can function as an AR androgen response. Aberrations in these processes can coactivator so that RB hyperphosphorylation at G1/S may facilitate androgen-independent cellular proliferation, and decrease AR activity. Cyclin E may also function as an may contribute to the development of recurrent tumors. AR coactivator, and its increased expression as cells Future investigations into the consequence of AR-cell move into S-phase may contribute to AR reactivation. In cycle crosstalk in prostate cancer are likely to lead to new any case, further studies are needed to confirm and avenues of therapeutic intervention. extend the results of this study. Acknowledgements Cell cycle regulation of AR protein The authors thank Dr. Clay Comstock, Dr. Erik Knudsen, Matt Schiewer, expression the S.P. Balk lab, and the K. Knudsen lab for ongoing discussions and critical reading of the manuscript. 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(2007) The regulation of cyclin D1 degradation: roles in cancer protein levels. Immunohistochemistry of cell lines in vitro, development and the potential for therapeutic invention Mol Cancer 6, and of in vivo prostate cancers, further showed loss of AR protein expression in mitotic cells. The authors suggest that AR in these cells is a licensing factor for Alt, J. R., Gladden, A. B. and Diehl, J. A. (2002) p21(Cip1) Promotes cyclin D1 nuclear accumulation via direct inhibition of nuclear export J DNA replication, and that this decline in AR protein is Biol Chem 277, 8517-23. required to license a new round of DNA replication. This decline is not observed in stromal cells, which are not Alt, J. R., Cleveland, J. L., Hannink, M. and Diehl, J. A. 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AR, the cell cycle, and prostate cancer

Balk, Steven P.; Knudsen, Karen E.
Nuclear Receptor Signaling , Volume 6 – Feb 1, 2008
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Abstract

Review Nuclear Receptor Signaling | The Open Access Journal of the Nuclear Receptor Signaling Atlas Steven P. Balk and Karen E. Knudsen Corresponding Author: [email protected] Cancer Biology Program-Hematology Oncology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA (S.P.B.) and Department of Cell and Cancer Biology (K.E.K.), Center for Environmental Genetics (K.E.K.), and UC Barrett Cancer Center (K.E.K.), University of Cincinnati College of Medicine, Cincinnati, Ohio, USA; Karen Knudsen’s new contact information, effective December 15th, 2007, is: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson Medical College, Philadelphia, Pennsylvania, USA The androgen receptor (AR) is a critical effector of prostate cancer development and progression. The dependence of this tumor type on AR activity is exploited in treatment of disseminated prostate cancers, wherein ablation of AR function (achieved either through ligand depletion and/or the use of AR antagonists) is the first line of therapeutic intervention. These strategies are initially effective, and induce a mixed response of cell cycle arrest or apoptosis in prostate cancer cells. However, recurrent, incurable tumors ultimately arise as a result of inappropriately restored AR function. Based on these observations, it is imperative to define the mechanisms by which AR controls cancer cell proliferation. Mechanistic investigation has revealed that AR acts as a master regulator of G1-S phase progression, able to induce signals that promote G1 cyclin-dependent kinase (CDK) activity, induce phosphorylation/inactivation of the retinoblastoma tumor suppressor (RB), and thereby govern androgen-dependent proliferation. These functions appear to be independent of the recently identified TMPRSS2-ETS fusions. Once engaged, several components of the cell cycle machinery actively modulate AR activity throughout the cell cycle, thus indicating that crosstalk between the AR and cell cycle pathways likely modulate the mitogenic response to androgen. As will be discussed, discrete aberrations in this process can alter the proliferative response to androgen, and potentially subvert hormonal control of tumor progression. Received September 14th, 2007; Accepted December 7th, 2007; Published February 1st, 2008 | Abbreviations: AR: androgen receptor; ARE: androgen response element; CAK: CDK activating kinase; CDK: cyclin dependent kinase; DHT: dihydrotestosterone; ER: estrogen receptor α; G1: gap phase 1; G2: gap phase 2; HDAC: histone deacetylase; M: the phase of mitosis; PPAR: peroxisome proliferator-activated receptor; PSA: prostate specific antigen; RB: retinoblastoma tumor suppressor; S: phase of DNA replication; TR: thyroid hormone receptor; TSA: trichostatin A | Copyright © 2008, Balk and Knudsen. This is an open-access article distributed under the terms of the Creative Commons Non-Commercial Attribution License, which permits unrestricted non-commercial use distribution and reproduction in any medium, provided the original work is properly cited. Cite this article: Nuclear Receptor Signaling (2008) 6, e001 prostate cancers, and this is considered an incurable Prostate cancer is dependent on stage of the disease. Given the dependence of prostate androgen action cancer cells on the androgen signaling axis, a concerted Prostatic adenocarcinoma is the most frequently effort has been undertaken to determine the diagnosed malignancy and second leading cause of mechanism(s) by which androgens induce prostate cancer cancer death amongst men in the United States [Jemal cell proliferation and survival. et al., 2005]. Localized prostate cancer can be definitively Androgen receptor regulation in prostate cancer treated by surgical resection or through radiation therapy [Catalona et al., 1999; Denmeade and Isaacs, 2002; Dorff Androgen exerts its biological effects through the et al., 2006; Swanson, 2006]. However, invasive or even androgen receptor (AR), a member of the nuclear receptor micrometastatic disease presents a clinical challenge, as superfamily that acts as a ligand dependent transcription these tumors respond poorly to standard cytotoxic factor [Evans, 1988; Mangelsdorf et al., 1995; Shand and regimens that act through genomic insult. Therefore, Gelmann, 2006; Trapman and Brinkmann, 1996]. prostate cancers are treated based on a unique Testosterone is the most abundant androgen in the sera, characteristic, in that they are exquisitely dependent on but in prostatic epithelia is converted to a more potent androgen for development, growth, and survival [Balk, androgen, dihydrotestosterone (DHT) through the action 2002; Culig and Bartsch, 2006; Jenster, 1999; Klotz, of a resident enzyme, 5α-reductase [Russell and Wilson, 2000]. Androgen ablation triggers cell death or cell cycle 1994; Wilson, 1996]. Prior to ligand binding, the AR is arrest of prostate cancer cells [Agus et al., 1999; held inactive through association with heat shock proteins Denmeade et al., 1996; Huggins and Hodges, 1972; and is precluded from DNA binding. Ligand binding Isaacs, 1984; Knudsen et al., 1998; Kyprianou and Isaacs, releases the inhibitory heat shock proteins, and the 1988]. Thus, androgen ablation remains the primary receptor rapidly translocates to the nucleus, where it binds course of treatment for all patients with metastatic disease DNA as a homodimer on androgen responsive elements [Jenster, 1999; Klotz, 2000; Loblaw et al., 2004; Sowery (AREs) within the regulatory regions of target genes et al., 2007]. These therapies are initially effective, and [Gelmann, 2002; Marivoet et al., 1992; Trapman and result in disease remission. However, recurrent tumors Brinkmann, 1996]. Furthermore, recruitment of arise within a median of 2-3 years, wherein androgen coactivators (which contain or recruit histone acetylases) signaling has been inappropriately restored [Feldman and chromatin remodeling complexes facilitate and Feldman, 2001]. At present, few therapeutic regimens transcriptional initiation, and AR-dependent gene have been described to effectively manage recurrent www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06001 | Page 1 of 12 Review AR-cell cycle crosstalk expression ensues [Gnanapragasam et al., 2000; Heinlein Feldman and Feldman, 2001; Leewansangtong and and Chang, 2002; Heinlein and Chang, 2004]. The Soontrapa, 1999; Taplin and Balk, 2004]. First line capacity of AR to subsequently induce a gene expression treatment ablates AR function through ligand depletion, program that promotes cell cycle progression is clearly as achieved through either bilateral orchiectomy or the dependent on cell context. For example, during use of GnRH agonists. Adjuvant or second line therapies development and homeostasis it is clear that the stromal involve the use of direct AR antagonists (e.g., AR plays a major role in stimulating epithelial cell bicalutamide) which utilize at least two mechanisms of proliferation; by contrast, it is hypothesized that a action [Chodak, 2005; Klotz, 2006] . First, these agents switching mechanism arises during tumorigenesis to compete for DHT binding. Second, selected AR render the proliferative function of AR cell autonomous antagonists trigger the recruitment of transcriptional in prostate cancer cells. The specific combinations of corepressors (e.g., NCoR) to AREs, thereby fostering cofactors recruited to AREs likely also provide a active repression of AR target gene expression [Shang mechanism for tissue specific and ligand specific gene et al., 2002]. At the cellular level, androgen ablation expression. Through these actions, it is apparent that the induces cell death or cell cycle arrest, which underpins AR promotes prostate cancer survival and proliferation tumor regression [Agus et al., 1999; Denmeade et al., in prostate cancer cells [Balk, 2002; Feldman and 1996; Huggins and Hodges, 1972; Isaacs, 1984; Knudsen Feldman, 2001]. et al., 1998; Kyprianou and Isaacs, 1988]. Effective AR inhibition is also observed by a loss of detectable serum While the subsets of AR target genes that underlie each PSA. However, this remission is transient, and tumor cellular outcome have yet to be clearly defined, discovery recurrence is almost invariably observed [Balk, 2002; of at least one major AR-dependent target gene, prostate Feldman and Feldman, 2001; Leewansangtong and specific antigen (PSA) [Riegman et al., 1991], has had a Soontrapa, 1999]. Recurrence is typically preceded by a major impact on disease management. Specifically, serum rise in PSA (also called “biochemical recurrence”) PSA is monitored clinically to detect early stage disease, [Feldman and Feldman, 2001; Klotz, 2000; Trapman and track tumor burden, monitor the efficacy of therapeutic Brinkmann, 1996], and this observation yielded some of intervention, and detect the emergence of recurrent the first evidence that tumor progression is associated tumors post-therapy [Nash and Melezinek, 2000; Ryan with inappropriately restored AR function, despite et al., 2006]. Thus, readouts of AR activity are critical for sustained androgen ablation and/or the use of AR the assessment of disease progression and therapeutic antagonists. AR re-activation in recurrent tumors occurs outcome. In addition, it has been recently discovered that through multiple mechanisms, including AR amplification, chromosomal translocations occur with significant AR mutation, ligand-independent AR activation, frequency in prostate cancer which render the potentially hypersensitivity to a low ligand environment, enhanced pro-proliferative ETS genes (ERG, ETV1, or ETV4) under local production of androgens, excessive production of control of the AR-induced TMPRSS2 promoter/enhancer AR coactivators, and/or as a result of signals that disrupt [Demichelis et al., 2007; Tomlins et al., 2005; Wang et AR corepressor function [Chmelar et al., 2007; Feldman al., 2007]. However, subsequent functional investigations and Feldman, 2001; Stanbrough et al., 2006]. Indeed, it suggest that the TMPRSS2-ETS fusions may principally is now well established that such “androgen independent” exert their effects through alteration of tumor phenotypes prostate cancer remains exquisitely dependent on AR other than cell proliferation. For example, overexpression function [Chen et al., 2004; Cheng et al., 2006; Yuan et of ETV1 in normal or transformed prostatic epithelia had al., 2006]. Since AR appears to be a key determinant of no impact on cellular proliferation rates or cell cycle prostate cancer growth and progression, it is imperative progression, but facilitated invasion of these models to dissect the mechanisms by which AR governs cellular [Tomlins et al., 2007]. Thus, the contribution of these proliferation in prostate cancer cells. fusions to alterations in cell cycle control has yet to be well resolved. Lastly, it is possible that non-genomic AR Mitogenic signaling and the cell cycle signaling may influence the proliferative program. It is machinery: an overview known that androgen stimulation in AR-positive cells can trigger rapid activation of the MAPK pathway, and thereby Transitions into and within the mitotic cell cycle are potentially induce a mitogenic response. Consistent with dictated by the coordinate activation of cyclin-dependent kinase (CDK)/cyclin complexes, wherein cyclin binding this idea, rapid androgen signaling was recently identified induces the catalytic activity of the kinase [Lee and as a major stimulus for meiotic progression in Xenopus oocytes, and has also been linked to muscle cell Sicinski, 2006; Malumbres and Barbacid, 2007; Sherr, proliferation [White et al., 2005; Yoshioka et al., 2006]. 1996; Sherr and Roberts, 2004]. Mitogenic signaling pathways generally induce cell cycle progression through Thus, while the mechanisms underpinning the capacity ordered activation of CDK-cyclin complexes, whereas of AR to induce a mitogenic program may be diverse and dependent on cell context, it is clear that ligand-dependent anti-mitogenic signals that result from extracellular events activation of AR is a limiting factor for engagement of the (e.g., nutrient depletion) or intracellular insults (e.g., DNA damage) typically serve to attenuate CDK function. cell cycle machinery in prostate cancer cells. Although the signals that dictate commitment to the cell Given these functions, inhibition of AR activity is the major cycle are often cell type-specific, the core machinery that therapeutic goal for management of metastatic disease, drives the cell cycle engine is well conserved. Prior to as achieved via multiple mechanisms [Balk, 2002; mitogenic stimulation cells can exit the cell cycle and www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06001 | Page 2 of 12 Review AR-cell cycle crosstalk enter into a resting stage deemed “G ”. At this stage, histone gene expression. Recent findings demonstrate several key gatekeepers of cell cycle transitions are that these activities are associated with both catalytic invoked to prevent unscheduled cell cycle progression. (CDK2 kinase dependent) and non-catalytic functions Paramount amongst these is activation of the [Geng et al., 2007; Lee and Sicinski, 2006]. Subsequently, retinoblastoma tumor suppressor protein (RB), which transition through the remainder of the cell cycle (G2 and assembles transcriptional repressor complexes on the M phase) is driven by ordered activation of CDK1-cyclin promoters of target genes that are required to initiate A and CDK1-cyclin B complexes [Shapiro, 2006]. Cyclin DNA replication (e.g., cyclin A, PCNA) [Knudsen and B production steadily rises in G2; once reaching a Knudsen, 2006]. Many such critical RB target genes are threshold level, mitotic entry ensues dependent on this primed for activation by residence of activator E2F/DP1 kinase. CDK1-cyclin B activity continues to increase complexes on the promoter regions, but the transcriptional throughout early mitosis until anaphase, wherein rapid repressor complexes recruited by RB (which include degradation of cyclin B (and thereby loss of CDK1 activity) histone deacetylases, SWI/SNF chromatin remodeling triggers mitotic exit and completion of the cell cycle [Pines, complexes and/or polycomb group proteins) act as potent 2006; Shapiro, 2006]. inhibitors of transcriptional activation [Johnson and To counterbalance this sophisticated coordination of Degregori, 2006]. Thus, mitogenic stimuli must act to CDK-cyclin activation, mechanisms exist to halt the cell balance RB function, and do so through activation of cycle in the presence of cellular insult. RB typically CDK-cyclin complexes. remains hyperphosphorylated/inactivated until mitotic Mitogenic stimuli typically trigger accumulation of D-type exit, when the “braking” action of the RB tumor suppressor cyclins (cyclins D1, D2, and/or D3), which can bind and is reset by phosphatase activity. However, many activate the early G1 kinases CDK4 or CDK6 [Lee and anti-proliferative signals result in RB Sicinski, 2006; Sherr and Roberts, 2004]. D-cyclin dephosphorylation/activation, thus inducing RB-dependent production is a tightly regulated process, which has been cessation of cell cycle progression. For example, DNA Cip1 most extensively studied with cyclin D1 [Alao, 2007; damage signals that induce p53-mediated p21 Gladden and Diehl, 2005; Knudsen, 2006]. The cyclin D1 induction to high levels can cause downregulation of transcript is controlled at the level of mRNA production, CDK2 activity and thereby prevent RB phosphorylation stability, splicing, and translation. Once produced, cyclin [Sherr and Roberts, 2004]. Alternatively, the related CDK2 Kip1 D1 action is subjected to further regulation at the level of inhibitor p27 is often induced by signals such as serum subcellular localization, targeted degradation, and CDK4/6 deprivation, thus acting through similar pathways to halt binding [Alt et al., 2000; Gladden et al., 2006]. These cell cycle progression [Nickeleit et al., 2007]. From these Cip1 latter processes appear to involve p21 , which was observations, it is apparent that the G1-S cell cycle originally classified as a CDK inhibitor. This classification machinery plays critical roles in the response to the intra- Cip1 may be overly simplistic, as while p21 can inhibit CDK2 and extracellular environments. While these general Cip1 complexes, p21 is conversely important for promoting principles are conserved in the majority of cell types, it is formation, activation and nuclear enrichment of increasingly apparent that different mitogenic cues utilize CDK4/6-cyclin D complexes [Alt et al., 2002; Cheng et disparate mechanisms to engage the cell cycle al., 1999; LaBaer et al., 1997; Sherr and Roberts, 1999]. machinery. Once active, the principal cell cycle function of CDK4/6-cyclin D complexes is to initiate RB AR governs the cyclin D-RB axis in phosphorylation. The concept that this is the major cell prostate cancer cells cycle function of CDK4/6 is supported by the observation Analyses of AR-dependent cell cycle progression in that RB-deficient tumor cells are resistant to cell cycle prostate cancer cells have shown that androgen is a arrest induced by inhibition of the kinase [Lukas et al., critical regulator of the G1-S transition (Figure 1). Prostate 1995]. Thus, loss of RB in cancer is proposed to bypass cancer cells deprived of androgen arrest in early G1 the requirement for this early event in cell cycle phase, concomitant with loss of cyclin D1 and cyclin D3 progression. expression, attenuated CDK4 activity (expression Although RB phosphorylation/inactivation is initiated by unchanged), and hypophosphorylated/activated CDK4/6, this only partially compromises the RB retinoblastoma tumor suppressor [Knudsen et al., 1998; Xu et al., 2006]. Recent studies revealed that androgen transcriptional repressor function [Knudsen and Knudsen, induces D-type cyclin expression via mTOR-dependent 2006]. Subsequent to this event, a downstream kinase (CDK2) is responsible for completing RB phosphorylation enhancement of translation [Xu et al., 2006]. The ability and thereby extinguishing its repressor function. Critically, of androgen to modulate cyclin D translation is distinct from mechanisms utilized by other hormones. For the requisite cyclins associated with CDK2, cyclins E and example, estrogen induces cyclin D1 transcription in A, are themselves regulated via RB-mediated transcriptional repression. Thus, CDK2-cyclin complexes breast cancer cells, through the ability of its cognate constitute a feed-forward mechanism to stimulate cell receptor (the estrogen receptor, ER) to directly modulate cyclin D1 regulatory regions [Eeckhoute et al., 2006; cycle progression through modulation of RB. In addition, Sabbah et al., 1999]. Thus, androgen regulation of early cyclin E- and cyclin A-assembled complexes impinge on additional substrates that promote activation of the DNA G1 events is specific to this class of hormone. replication machinery, centrosome duplication, and www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06001 | Page 3 of 12 Review AR-cell cycle crosstalk Figure 1. AR-cell cycle crosstalk. Activated AR stimulates the accumulation of cyclin D1 (D1), through mammalian Target of Rapamycin (mTOR), Cip1 to activate CDK4 and promote phosphorylation of the retinoblastoma (RB) tumor suppressor. In addition, AR-induced expression of p21 and Kip1 degradation of p27 further enhance cycD1/CDK4 and cycE/CDK2-dependent inactivation of RB and allow expression of E2F target genes like cyclin A (CycA). Cyclin A in turn activates CDK2 to drive G1-S phase transition. Subsequently engaged components of the cell cycle machinery then impinge on AR to regulate the androgen response. Elevated cyclin D1 acts as in a negative feedback loop to attenuate AR activity, thereby modulating androgen action. In G2-phase, CDK1 promotes the phosphorylation and activation of AR. However, AR is degraded in M-phase and is purposed to be a “licensing factor” for DNA replication. Components that suppress AR function are outlined in red, whereas positive effectors of AR activity are outlined in green. Cip1 In contrast to the D-type cyclins, cyclin E levels remain examination of p21 in prostate cancer has revealed relatively unchanged by androgen withdrawal, indicating that expression is enhanced in tumors, and correlates that alteration of cyclin E expression is not a major with a higher proliferative index and Gleason grade mechanism of androgen action [Knudsen et al., 1998; Xu [Aaltomaa et al., 1999; Baretton et al., 1999]. et al., 2006]. However, cyclin A levels and overall CDK2 To date, these observations culminate in a model wherein activity are diminished upon androgen ablation. These androgen induces cyclin D1 accumulation through mTOR, data are consistent with the observation that androgen promotes active CDK4/cyclin D1 assembly (potentially depletion invokes RB activity, as cyclin A is a Cip1 through p21 induction), and facilitates CDK2 activation well-established target of RB-mediated transcriptional Kip1 through degradation of p27 . These collective events repression. Furthermore, androgen depletion induces Kip1 result in RB phosphorylation, de-repression of cyclin A p27 , which likely contributes to the observed reductions expression, and S-phase progression. Based on this in CDK2 activity [Knudsen et al., 1998]. This supposition knowledge of AR function, it could be hypothesized that is consistent with more recent findings which Kip1 aberrations in the cyclin D-RB axis in cancer could demonstrated that low p27 expression is predictive for supplant the requirement for androgen and contribute to shorter time to disease recurrence in prostate cancer Kip1 disease progression. Investigations challenging this [Halvorsen et al., 2003]. Similarly, p27 loss in the hypothesis have revealed a significant function for RB in context of a PTEN mutation promotes a tumorigenic controlling the response to androgen ablation therapy, phenotype in the prostate [Gao et al., 2004]. Interestingly, Kip1 and unique crosstalk mechanisms between the AR and upon re-stimulation with androgen, p27 is degraded Cip1 cell cycle pathways that assist in coordinating and/or [Ye et al., 1999]. By contrast, p21 expression is lost maintaining androgen-dependent cellular proliferation. upon androgen ablation in prostate cancer cells in vitro, which correlates with a higher proliferative index in human RB function in prostate cancer and the tumor specimens [Knudsen et al., 1998; Kolar et al., Cip1 2000]. Thus, p21 correlates with androgen stimulation response to AR-directed therapeutics and mitogenic proliferation in prostate cancer. As discussed above, CDK-mediated RB Cip1 Remarkably, p21 has been validated as a direct AR phosphorylation/inactivation is a key component of the target gene [Lu et al., 1999], and its induction upon proliferative response to AR. These findings suggest that androgen stimulation may assist in assembling active RB loss may play an influential role in prostate cancer CDK4/cyclin D1 complexes. In agreement with this, www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06001 | Page 4 of 12 Review AR-cell cycle crosstalk development and/or the response to AR-directed the ability of AR to control the G1-S transition is likely a therapeutics. Consistent with this concept, RB is lost or critical component for maintaining androgen dependence. inactivated in approximately 30-60% of prostatic While these studies highlight the importance of AR in adenocarcinomas through disparate mechanisms [Brooks governing the cell cycle machinery, it is becoming et al., 1995; Ittmann and Wieczorek, 1996; Jarrard et al., increasingly apparent that substantive crosstalk between 2002; Tricoli et al., 1996]. Accordingly, several model the AR and cell cycle pathways may also contribute to systems have been developed to more directly probe the this process. importance of RB function in this tissue. Transgenic mouse models wherein RB and p53 are inactivated by Cell cycle regulation of AR SV40 large T- and small T-antigen overexpression in the Only a small number of studies have directly examined luminal epithelia result in high grade PIN and/or prostate the influence of cell cycle on AR activity. Nonetheless, cancer (often with neuroendocrine phenotypes) and can many of the proteins found to interact with or modulate achieve androgen independence after castration [Gingrich AR are also regulated during the cell cycle. These include et al., 1997; Greenberg et al., 1995]. Tissue recombination proteins whose expression or activity are increased in G studies showed that RB-deficient prostatic epithelia give (RB), G1 to S phase (cyclin D1, cyclin E, Cdk6), or G2 rise to hyperplastic disease in 40% of grafted samples (Cdk1). Therefore, it appears likely that AR activity is when recombined with wild-type rat urogenital modulated during the cell cycle through interactions with mesenchyme [Wang et al., 2000]. Similarly, conditional one or more of these proteins. Moreover, AR may be RB deletion in the prostate resulted in focal hyperplasia further modulated directly during the cell cycle by that is potentially reminiscent of early stage disease transcriptional or post-transcriptional mechanisms, the [Maddison et al., 2004b]. These effects are exacerbated latter including alterations in phosphorylation, acetylation, by combinatorial p53 deletion, which results in rapidly or ubiquitination that affect transcriptional activity or progressing metastatic carcinomas of the prostate [Zhou stability. The sections below first outline reported et al., 2006]. Together, these data are indicative that interactions between AR and cell cycle regulated proteins, inactivation of RB may prime prostate cells to become and then describe studies that have directly examined cancerous when subjected to other insults. AR during the cell cycle. In addition to these observations, emerging evidence Retinoblastoma protein (RB) suggests that RB inactivation may also subvert or weaken Direct interactions between AR and RB have been the requirement for AR-mediated cell cycle progression. reported by two groups based on GST-RB and Although studies are few in number, one study showed mammalian two-hybrid protein interaction approaches that RB mRNA expression was low in 36% of patients that failed combined androgen blockade [Mack et al., [Lu and Danielsen, 1998; Yeh et al., 1998]. The interacting site on the AR was mapped to the AR N-terminal domain. 1998]. Furthermore, by FISH analysis it was reported that Overexpression of RB enhanced AR transcriptional RB loss is almost four times more frequent after hormone activity, while AR transcriptional activity was lost in cells therapy [Kaltz-Wittmer et al., 2000]. Since these data indicate that RB inactivation and/or deletion may facilitate that were RB-negative and was decreased in cells expressing RB-binding oncogenes. Interestingly, RB has the transition to androgen independence, a recent study also been reported to interact with the GR, and RB challenged this hypothesis in vitro, through overexpression can similarly enhance GR transcriptional shRNA-mediated depletion of RB in AR-dependent prostate cancer cells [Sharma et al., 2007]. In these activity [Singh et al., 1995]. However, in contrast to AR, the GR remains transcriptionally active in RB deficient models, RB depletion did not confer a proliferative cells [Lu and Danielsen, 1998]. Significantly, the GR advantage in the presence of androgen; rather coactivation by RB is dependent on Brm, with RB and RB-deficient cells failed to elicit a cytostatic response (as compared to RB-positive isogenic controls) when Brm forming a complex and both being required for GR coactivation [Singh et al., 1995]. It is not clear whether a challenged with androgen ablation, AR antagonists, or similar mechanism mediates RB coactivation of AR. combined androgen blockade. Not yet considered, however, is whether loss of RB or deregulation of G1-S AR has also been found to interact directly with an alleviates the need for unliganded AR, and this RB-associated protein, retinoblastoma-associated Kruppel determination is the focus of ongoing projects. However, protein (RbaK) [Hofman et al., 2003]. RbaK contains a studies examining the impact RB loss were subsequently Kruppel-associated box (KRAB) repressor motif at its extended to determine the impact of RB loss on the N-terminus, in conjunction with multiple Kruppel type zinc response to second line chemotherapeutic intervention, finger domains, and contributes to the RB-dependent as reports in other cell systems have suggested that loss regulation of E2F transcription factors. RbaK interacts of RB-dependent DNA damage checkpoints can sensitize directly with RB and appears to interact independently cells to cytotoxic agents [Harrington et al., 1998; Knudsen with the AR LBD based on mammalian-two hybrid and et al., 1998]. Indeed, RB-depleted prostate cancer cells coimmunoprecipitation experiments, with the interaction demonstrated enhanced susceptibility to cell death being androgen-independent. Although RbaK contains induced by a select subset of chemotherapeutic agents. the KRAB repressor motif, overexpression enhances AR Combined, these data indicate that RB status may be an transcriptional activity by unclear mechanisms. Further important determinant of the response to AR-directed studies are needed to determine precisely how RB and therapeutic strategies against prostate cancer, and that www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06001 | Page 5 of 12 Review AR-cell cycle crosstalk RbaK modulate AR activity, and to determine the AR activity and androgen-dependent proliferation in biological significance of these interactions for AR activity, AR-positive prostate cancer cells [Petre-Draviam et al., particularly in RB negative PCa [Sharma et al., 2007]. 2003]. As expected, AR-negative prostate cancer cells are refractory to the repressor function of cyclin D1 [Burd D-cyclins et al., 2006]. These data are consistent with observations that AR activity is highly regulated as a function of the Although androgen stimulates cyclin D1 accumulation cell cycle, wherein cyclin D1 levels inversely correlate and concomitant CDK4 activation [Knudsen et al., 1998; with AR activity [Martinez and Danielsen, 2002]. Xu et al., 2006], restoration of cyclin D1 expression under Moreover, in a mouse model of prostate cancer, cyclin conditions of androgen ablation is insufficient to drive D1 levels decrease as a function of progression, whereas androgen-independent proliferation [Fribourg et al., 2000]. cyclin E levels are elevated; this observation led to the Moreover, it was observed that modest elevations of hypothesis of a putative “cyclin switch” that may occur in cyclin D1 in the presence of androgen inhibit (rather than prostate cancer progression [Maddison et al., 2004a] , enhance) cellular proliferation [Burd et al., 2005; although this concept has yet to be validated in human Petre-Draviam et al., 2003]. This unexpected capacity of specimens. Based on these collective observations, it is cyclin D1 to attenuate cell cycle progression is specific hypothesized that cyclin D1 serves as a “negative to AR-positive prostate cancer cells, thus suggesting a feedback switch” to modulate androgen-dependent gene putative relationship between cyclin D1 and AR function. expression and concomitant cellular proliferation, thereby Detailed examination of this interaction revealed an governing the strength and duration of the androgen unexpected and unique role of cyclin D1 in control of AR response. Recent analyses indicated that these activity. “balancing” functions of cyclin D1 are disrupted in prostate cancer [Burd et al., 2006; Comstock et al., 2007; In addition to its ability to modulate CDK4 kinase activity, Knudsen, 2006]. In the context of normal prostatic increasing evidence has demonstrated that cyclin D1 epithelia, the role of AR is to suppress cell proliferation harbors CDK-independent functions in controlling transcription factor action [Coqueret, 2002]. Cyclin D1 and drive differentiation. While not yet examined, it is possible that cyclin D1 may be important for suppressing can directly interact with and modulate a large number these functions to allow for entry into the cell cycle. of transcription factors, including v-Myb, DMP1, Sp-1, and MyoD. A landmark paper demonstrated the relevance Cdk6 of cyclin D1-mediated transcriptional regulation, wherein it was shown that the ability of cyclin D1 to interact with One study found that AR could be coactivated by and modulate the CCAAT/enhancer binding protein (and transfected Cdk6 [Lim et al., 2005]. Importantly, this repress a large subset of genes) has a major coactivation was not due to sequestration of cyclin D1, consequence in human tumors [Lamb et al., 2003]. In as it was observed in cyclin D1-deficient NIH3T3 cells. addition, it has been recently shown that “kinase Moreover, coactivation was not prevented by a mutation independent” functions of cyclin D1 underlie mammary in Cdk6 that prevents cyclin D1 binding, or by point gland development, in that in vivo knock-in of cyclin D1 mutations that prevent binding of p16INK4a or inhibit mutants that are unable to activate CDK4 can effectively catalytic activity. Cdk6 was further shown to bind AR reverse the mammary gland phenotype observed in cyclin based on coimmunoprecipitation of transfected AR and -/- D1 mice [Landis et al., 2006]. Thus, the Cdk6, and this interaction was similarly not blocked by CDK4-independent functions of cyclin D1 appear to serve the above mutations that prevent cyclin D1 and p16INK4a critical cellular functions. binding, or catalytic activity. Stable transfection of Cdk6 into LNCaP cells could enhance androgen stimulated The largest class of transcription factors known to be growth and expression of the androgen regulated PSA modulated by cyclin D belong to the nuclear receptor gene. Finally, ChIP experiments indicated that Cdk6 was superfamily, including ER (estrogen receptor α), TR part of the AR transcriptional complex that assembles on (thyroid hormone receptor), PPARγ and AR [Coqueret, the PSA gene. Further studies are clearly needed to 2002; Ewen and Lamb, 2004]. In the case of AR, cyclin determine the molecular basis for this kinase independent D1 binds directly to the N-terminus of the receptor and AR coactivation by Cdk6. Interestingly, Cdk6 expression blocks conformational changes that are required for in androgen-sensitive prostate cancer cells increases in maximal AR activity upon ligand activation (N-C response to androgen as cells move from G1 to S phase, interaction) [Burd et al., 2005; Petre-Draviam et al., 2005]. which may then provide a positive feedback loop to further Moreover, cyclin D1 associates with histone deacetylase enhance AR activity [Bai et al., 2005]. 3 (HDAC3), and recruitment of HDAC activity is essential for its corepressor functions [Lin et al., 2002; Cyclin E Petre-Draviam et al., 2005]. These actions of cyclin D1 Cotransfection studies carried out with AR, ARE-CAT are independent of CDK activity, and a repressor domain reporter, and cyclin D1, E, and A showed that cyclin E within the protein (encoded by amino acids 142-253) has could specifically enhance androgen-stimulated been identified which is capable of supporting both cyclin transcriptional activity [Yamamoto et al., 2000]. This D1 corepressor functions [Petre-Draviam et al., 2005]. coactivation was not dependent on cyclin E binding to The biological consequence was shown in that even Cdk2, was independent of cell cycle progression, and modest induction of cyclin D1 levels (at stoichiometric was not observed for GR or PR. Cyclin E transfection into levels with the receptor) are sufficient to suppress both www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06001 | Page 6 of 12 Review AR-cell cycle crosstalk LNCaP cells similarly enhanced expression of the Cdk1 endogenous PSA gene. An interaction between AR and Cdk1 is activated in the G2 phase of the cell cycle and is cyclin E was demonstrated by mammalian two-hybrid the critical Cdk required for mitosis. As noted above, Cdk1 protein interaction assays and by coimmunoprecipitation associates with cyclin B and is then activated by removal of transfected proteins. The interaction was mapped to of inhibitory phosphates (mediated by Cdc25 isoforms) the AR N-terminal domain, and GST pulldowns indicated and by an activating T loop phosphorylation mediated by that cyclin E was interacting with a domain at the Cdk7. The unliganded AR is phosphorylated primarily at C-terminal end of the AR N-terminal domain (amino acids one serine-proline site in the N-terminal domain (Ser-94), 419-556). As above, further studies are needed to and is phosphorylated at multiple additional Ser-Pro sites determine how cyclin E mediates AR coactivation and in response to androgen [Gioeli et al., 2002; Kuiper and whether this interaction may contribute to PCa Brinkmann, 1995; Zhou et al., 1995]. These are candidate development or progression. sites for Cdk1 and other proline-directed kinases, and studies using Cdk1 transfection and Cdk inhibitors CDK-activating kinase (CAK)/Cdk7 indicate that Cdk1 phosphorylates at least one site in the CDK-activating kinase (CAK), composed of Cdk7, cyclin AR N-terminus (Ser-81) [Chen et al., 2006]. Significantly, H, and MAT1, mediates the phosphorylations of both transfection of cells with activated Cdk1 was found to Cdk2 and Cdk1 that are required for full activation and enhance the stability and transcriptional activity of AR. cell cycle progression. CAK is also a component of the Conversely, Cdk1 inhibitors decreased AR expression transcriptional machinery, and can mediate and transcriptional activity, although these drugs are not phosphorylation of ER and RAR [Rochette-Egly et al., highly specific for Cdk1 and may also effect AR by 1997; Trowbridge et al., 1997]. Immunoblotting of anti-AR targeting other Cdks such as Cdk7 [Chen et al., 2006]. immunoprecipitates identified the TFIIH transcription Although Cdk1 phosphorylates AR, site directed factor complex, which contains CAK, and further mutagenesis of Ser-81 and of additional Ser-Pro did not experiments demonstrated an interaction between AR block the ability of Cdk1 to stabilize AR, indicating that and CAK [Lee et al., 2000]. Transfection of the individual multiple sites may mediate this effect or that Cdk1 CAK proteins could weakly enhance AR transcriptional stabilizes AR by an indirect mechanism. activity, with greater coactivation when all three components were cotransfected. Coprecipitation Interestingly, an analysis of PCa clinical samples from experiments in vitro with S-labeled CAK proteins patients who had relapsed after androgen deprivation indicated that Cdk7 and cyclin H could interact with the therapy showed that cyclin B1, cyclin B2, and Cdk1 were AR N-terminal domain. These studies support the the most highly overexpressed cell cycle regulatory genes conclusion that TFIIH, as a general transcription factor, relative to primary untreated tumors [Stanbrough et al., interacts with AR. However, further studies are needed 2006]. As noted above, both Cdc25B and Cdc25C were to determine whether CAK phosphorylates AR or also found to be increased in higher grade prostate cancer selectively enhances its activity, or whether it directly and in tumors that relapsed after androgen deprivation modulates AR during the cell cycle. therapy [Ngan et al., 2003; Ozen and Ittmann, 2005]. Cyclin B expression also increases with disease Cdc25B progression in the murine TRAMP model of prostate cancer [Maddison et al., 2004a]. Taken together, these The Cdc25 dual function phosphatases (Cdc25A, B, and observations suggest that Cdk1 may contribute to AR C) mediate the activation of Cdk1 by removal of inhibitory activation in advanced cancers. In support of this phosphates from Thr-14 and Tyr-15. The exact functions hypothesis, the AR activation mediated by low levels of of each Cdc25 isoform are not yet clear, but recent data DHT in C4-2 cells (a subline of LNCaP cells that is indicate that Cdc25B specifically dephosphorylates and hypersensitive to low androgen levels) could be blocked activates cyclin B-Cdk1 complexes on centrosomes by treatment with a Cdk inhibitor [Chen et al., 2006]. [Lindqvist et al., 2005]. Significantly, Cdc25B has also been identified as a steroid receptor coactivator that can Direct assessment of transcriptional AR enhance the activity of ER, PR, GR, and AR [Ma et al., 2001; Ngan et al., 2003]. Cdc25B can interact directly activity during the cell cycle with these steroid receptors and stimulate their activity One study has directly examined modulation of AR in a cell-free transcription system. Surprisingly, this transcriptional activity during the cell cycle [Martinez and stimulation is not dependent on Cdc25B phosphatase Danielsen, 2002]. In this study, AR transcriptional activity activity, and its molecular basis remains unclear. in L929 cells (which express an endogenous AR) was Interestingly, both Cdc25B and Cdc25C were increased examined using integrated ARE regulated reporter genes in higher grade prostate cancer, with Cdc25C and a novel (MMTV-CAT and probasin-CAT). This study found that activated splice variant being further increased in PCa AR transcriptional activity (but not GR activity) was that relapses after androgen deprivation therapy [Ngan markedly decreased at the G1/S transition, and was et al., 2003; Ozen and Ittmann, 2005]. The interaction regained during S-phase. AR protein level was also with AR suggests that Cdc25B may contribute to PCa reduced at the G1/S transition, but this decrease was not progression both through effects on AR activation and as marked as the loss of transcriptional activity. A possible cell cycle. mechanism for the decreased AR expression during G1/S is increased E2F1, which has been found to suppress www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06001 | Page 7 of 12 Review AR-cell cycle crosstalk AR gene expression through binding to the AR promoter activities towards AR are not known to be cell [Davis et al., 2006]. cycle-regulated. Interestingly, Cdk1 has been reported to stabilize AR protein, although it is not clear whether Significantly, an HDAC inhibitor (TSA) could partially this is due to direct AR phosphorylation or other indirect restore AR transcriptional activity at the G1/S transition mechanisms [Chen et al., 2006]. Therefore, the decline without increasing AR protein levels. One interpretation in Cdk1 activity that occurs at the end of mitosis may of this result is that AR recruitment of coactivator proteins contribute to the marked increase in AR degradation that with HAT activity becomes limiting at the G1/S transition, is observed in early G1. resulting in decreased histone or AR acetylation. However, while histone acetylation can enhance Conclusions transcription, the role of AR acetylation in regulating AR The clinical challenges in prostate cancer center on activity is not clear [Popov et al., 2007]. Moreover, more controlling the action of the AR, which is required for both recent data show that HDAC inhibitors decrease AR tumor development and disease progression. Selective expression through inhibition of Hsp90, which must be pressure brought on by androgen ablation typically results deacetylated by HDAC6 for activity [Kovacs et al., 2005]. in a bypass mechanism to activate the receptor in the In any case, the multiple functions of HDACs make it absence of ligand, and thereby restore AR-dependent difficult to clearly assess their roles in regulating AR cellular proliferation. Thus, dissecting the mechanisms activity during cell cycle. by which AR governs cell cycle progression is instrumental for the design of new strategies to treat One possible mediator of this loss of AR transcriptional recurrent disease. It is apparent that activated AR governs activity at the G1/S transition is clearly cyclin D1, which the G1-S progression, and emerging evidence indicates increases during G1 to S progression and can function that cross talk between AR and the downstream cell cycle as a potent AR corepressor (see above). A second machinery serves a critical role in modulating the possible mediator is RB, which can function as an AR androgen response. Aberrations in these processes can coactivator so that RB hyperphosphorylation at G1/S may facilitate androgen-independent cellular proliferation, and decrease AR activity. Cyclin E may also function as an may contribute to the development of recurrent tumors. AR coactivator, and its increased expression as cells Future investigations into the consequence of AR-cell move into S-phase may contribute to AR reactivation. In cycle crosstalk in prostate cancer are likely to lead to new any case, further studies are needed to confirm and avenues of therapeutic intervention. extend the results of this study. Acknowledgements Cell cycle regulation of AR protein The authors thank Dr. Clay Comstock, Dr. Erik Knudsen, Matt Schiewer, expression the S.P. Balk lab, and the K. Knudsen lab for ongoing discussions and critical reading of the manuscript. AR protein expression during the cell cycle has been examined in one study, which used dual-color flow References cytometry to assess AR expression versus binding of Aaltomaa, S., Lipponen, P., Eskelinen, M., Ala-Opas, M. and Kosma, V. Hoechst dye [Litvinov et al., 2006]. Importantly, binding M. (1999) Prognostic value and expression of p21(waf1/cip1) protein in of the Hoechst dye is lowest in cells that have just exited prostate cancer Prostate 39, 8-15. mitosis, and prostate cancer cells (LNCaP, CWR22Rv1, and LAPC-4) with the lowest Hoechst dye staining had Agus, D. B., Cordon-Cardo, C., Fox, W., Drobnjak, M., Koff, A., Golde, D. W. and Scher, H. I. (1999) Prostate cancer cell cycle regulators: no detectable AR by flow cytometry. Sorting of this response to androgen withdrawal and development of androgen population with the lowest Hoechst dye binding, followed independence J Natl Cancer Inst 91, 1869-76. by AR immunoblotting, confirmed extremely low AR Alao, J. P. (2007) The regulation of cyclin D1 degradation: roles in cancer protein levels. Immunohistochemistry of cell lines in vitro, development and the potential for therapeutic invention Mol Cancer 6, and of in vivo prostate cancers, further showed loss of AR protein expression in mitotic cells. The authors suggest that AR in these cells is a licensing factor for Alt, J. R., Gladden, A. B. and Diehl, J. A. (2002) p21(Cip1) Promotes cyclin D1 nuclear accumulation via direct inhibition of nuclear export J DNA replication, and that this decline in AR protein is Biol Chem 277, 8517-23. required to license a new round of DNA replication. This decline is not observed in stromal cells, which are not Alt, J. R., Cleveland, J. L., Hannink, M. and Diehl, J. A. 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