Abstract
Androgens are critical for normal prostate development and function, as well as prostate cancer initiation and progression. Androgens function mainly by regulating target gene expression through the androgen receptor (AR). Many studies have shown that androgen-AR signaling exerts actions on key events during prostate carcinogenesis. In this review, androgen action in distinct aspects of prostate carcinogenesis, including (i) cell proliferation, (ii) cell apoptosis, and (iii) prostate cancer metastasis will be discussed.
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Key words
- Androgen receptor
- prostate cancer
- androgen metabolism
- androgen signaling
- castration-resistant prostate cancer
1 Androgen Signaling
Androgens are the male sex hormones, which control the differentiation and maturation of male reproductive organs, including the prostate gland. Testosterone is the principal androgen in circulation and is synthesized by Leydig cells in the testes, under the regulation of luteinizing hormone (LH), which is further regulated by gonadotropin-releasing hormone (GnRH). Adrenal glands also synthesize a small amount of androgens, such as dehydroepiandrosterone (DHEA) and androstenedione (4-dione) (1). Testosterone enters prostate cells by passive diffusion, where it is converted enzymatically by 5-α reductases to the more potent androgen dihydrotestosterone (DHT) (2). Binding of androgens to the androgen receptor (AR), a ligand-modulated transcription factor, induces a conformational change in the AR, causing release of heat shock proteins and translocation of the AR to the nucleus, where it transcriptionally regulates the expression of target genes (3).
In addition to the classic genomic effects of sex steroids, accumulating data have also shown the importance of nongenomic effects (4–7). For instance, androgen treatment results in the association of AR with Src kinase, and thereby activates Src/Raf-1/Erk pathway, leading to cell proliferation and survival (8). Androgens may also post-transcriptionally regulate gene expression by modulating the stability of mRNAs (6). Membrane androgen receptors may also account for some nongenomic effects of androgens (9).
2 Androgen and Prostate Carcinogenesis
Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer-related death in US men. The American Cancer Society has estimated that in the USA the number of new cases diagnosed in 2009 was 192,280, and about 27,360 men died of this disease (10). The problem is even more substantial when viewed from a global perspective, with prostate cancer accounting for more than 220,000 deaths worldwide every year (11). Multiple signaling pathways have been demonstrated to be critical for prostate cancer initiation and progression (12, 13), with the androgen signaling pathway being one of the most prominent.
Since the landmark research of Huggins and Hodges in the 1940s, it has been postulated that androgens promote prostate carcinogenesis (14, 15). Although it is well accepted that androgens are critical for prostate cancer growth, it is still controversial whether androgens promote human prostate carcinogenesis in vivo. Indeed, there is no increased incidence of prostate cancer in men administered testosterone, there is no reduced risk of prostate cancer in men with low serum androgen levels, and there is no correlation between prostate cancer and serum androgen levels (16, 17). Taken together, these data suggest a ‘saturation’ model of androgen action on androgen-dependent growth (18). This model states that physiologic levels of androgen are important for both normal and malignant prostate cell proliferation, but excessive androgens alone do not lead to uncontrolled cell proliferation. On the other hand, ligand-independent activation of AR signaling plays a critical role in initiation and progression of prostate cancer, particularly following androgen ablation therapy (19, 20). The role of ligand-independent AR activation in prostate carcinogenesis and progression has been discussed in several excellent reviews (1, 21, 22). The present review focuses on the effects of androgen signaling during critical phases of prostate carcinogenesis.
3 Androgen Action on Prostate Cell Proliferation
Although epidemiologic data suggest that androgens alone are not sufficient to promote prostate carcinogenesis (23), abundant biological data have demonstrated that androgens promote prostate cancer cell proliferation. Androgens induce prostate epithelial cell proliferation via multiple ways, either directly or indirectly.
One of the most common genetic alterations in prostate cancer is the fusion between two genes, i.e., the TMPRSS2 gene and the ETS transcription factor genes, ERG or ETV1 (24). ETS transcription factors are involved in multiple processes, including cell proliferation and cancer cell invasion (25). Current data suggest that up to 72% of all prostate cancers harbor a TMPRSS2-ETS translocation (26–28). TMPRSS2 is a membrane-bound serine protease, which is regulated by androgens and overexpressed in prostate cancers (29, 30). In addition, TMPRSS2 expression is largely limited to prostate, more specifically, prostate luminal epithelial cells (31, 32). The ERG gene is the most commonly overexpressed proto-oncogene in prostate cancer but the underlying mechanism of ERG overexpression was not clear (33). The finding of TMPRSS2-ETS translocations suggests that androgens may promote the expression of ETV1 and ERG, contributing to prostate carcinogenesis. A recent study shows that androgens and irradiation synergistically induce the translocations of TMPRSS2-ERG and TMPRSS2-ETV1 (34). Liganded AR can induce juxtaposition of translocation loci by triggering intra- and inter-chromosomal interactions. Such interactions appear to promote stress-induced site-specific DNA double-stranded breaks at these translocation loci by recruiting activation-induced cytidine deaminase and LINE-1 repeat-encoded ORF2 endonuclease, which are critical for chromosomal translocations. These results suggest a potential mechanism by which androgens promote prostate carcinogenesis through inducing gene translocation.
Increased levels of growth factors, such as insulin-like growth factors (IGFs), fibroblast growth factors (FGFs), and epidermal growth factors (EGFs), are associated with prostate cancer (35–37). Increased expression of growth factors and their receptors promotes prostate cell proliferation, migration, and tumor angiogenesis, thereby facilitating prostate carcinogenesis and cancer progression. IGF-1 has been shown to promote prostate cancer cell proliferation in vitro and facilitate the progression of a prostate cancer xenograft to a castration-recurrent state (35). Androgens regulate the expression of both IGF-1 (38) and its receptor IGF-1R (39) (Fig. 2.1). Two androgen response elements (AREs) exist within the IGF-1 promoter, suggesting that androgens regulate IGF-1 via a direct transcriptional mechanism (38). On the other hand, the effects of androgen on the expression of IGF-1R appear to be through a nongenomic event. Quantitative RT-PCR demonstrated that IGF-1R induction is independent of AR DNA-binding activity. Rather, it appears to depend on the Src/MAPK pathway. Androgen treatment activates Erk1/2 within 5 min, and inhibition of Src/MAPK signaling pathway by various methods can block androgen-induced Erk1/2 activation and IGF-1R expression (39). Another way by which androgens modulate the IGF-1 signaling pathway is through regulation of IGF-binding protein (IGFBP) expression. For example, IGFBP-5 is transcriptionally regulated by androgens (40). Data on androgen regulation on IGFBP-3 are controversial. Some reports have shown that androgens suppress IGFBP-3 levels (41, 42), whereas other studies have reported that androgens increase IGFBP-3 expression (43).
Androgen action on IGF-1 signaling. IGF-1 interacts with IGF-1R to induce PI3K/AKT activation, which then regulates the activities of mTOR and FOXO1. The androgen–AR complex affects IGF-1 signaling via multiple ways, either in a transcription activity-dependent or transcription activity-independent manner. Dashed line indicates that the underlying mechanism is not fully elucidated.
FGF8 is another androgen-regulated growth factor (44). The tumorigenic effect of FGF8 has been demonstrated in both cell culture and transgenic mice (45, 46). FGF8 protein is overexpressed in human prostate cancers (47), and the level of expression correlates with tumor stage, pathological grade, and disease-specific survival (48). FGF8b protein expression is correlated with the AR expression in prostate cancer tissues and castration of mice significantly increases FGF8b expression in CWR22 prostate cancer xenografts, suggesting a role of androgen in the regulation of FGF8 expression. Indeed, androgens regulate FGF8 expression at the transcriptional level (49).
Prostate tumors also exhibit aberrant expression of EGF and EGF receptors (50–52). EGF signaling appears to be essential for the androgen-induced proliferation of LNCaP prostate cancer cells, since small molecule inhibitors against tyrosine kinase activity of the EGF receptor can completely suppress androgen-induced proliferation of these cells (52). Members of the EGF receptor family (ERBB1/EGFR, ERBB2, ERBB3, and ERBB4) may be differentially regulated by androgens. While androgens enhance the expression of EGFR, they reduce expression of ERBB2 in LNCaP cells (52, 53), suggesting that androgens regulate EGFR and ERBB2 via different mechanisms. The stimulation of EGFR gene expression by androgens appears to be at the transcriptional level, since androgen-induced EGFR upregulation does not require de novo protein synthesis. In contrast, androgen-induced reduction of ERBB2 does require de novo protein synthesis, suggesting that this repression is an indirect effect of androgens (53). Surprisingly, EGFR and ERBB2 expression in castration-recurrent 22Rv1 cells is not affected by androgen treatment. This discrepancy is most likely due to the presence of ARΔCTD, a constitutively active form of AR, in 22Rv1 cells (53). ARΔCTD is encoded by a splice variant mRNA of the AR gene, which has a novel exon 2b (54). Constitutively active AR variants promote expression of AR-regulated genes and cancer cell proliferation in the absence of androgens (54, 55). Taken together, these data suggest that AR regulates EGF/EGFR signaling during prostate cancer progression through either ligand-dependent or ligand-independent mechanisms.
Besides the regulation of growth factors and their receptors, androgens have also been shown to crosstalk with the downstream effectors of growth factor signaling, such as PI3K/AKT. The PI3K/AKT pathway is one of the most frequently altered signaling pathways in a variety of human cancers and plays a critical role in prostate carcinogenesis and its progression (56, 57). Constitutively activated AKT has been found frequently in prostate cancer cell lines and tissues, mostly due to loss of PTEN function (57). PTEN is a phosphatase which dephosphorylates PIP3, thereby inhibiting PI3K-induced AKT activation. Loss of function of PTEN may be due to gene mutations (58), loss of heterozygosity (59), or gene deletions (60) in prostate cancers. Loss of function of PTEN and activation of AKT are significantly correlated with the progression of prostate cancer (61). Androgen-independent prostate cancer cell proliferation is correlated with increased activity of PI3K/AKT, suggesting a role of AKT in progression to castration-recurrent prostate cancers (CRPC) (62). Moreover, heterozygous PTEN+/– mice develop low-grade PIN lesions in their prostates, while PTEN hy/− mutants (harboring a hypomorphic allele with decreased PTEN expression) develop high-grade PIN lesions and locally invasive carcinomas (63). Moreover, loss of function of both PTEN and Nkx3.1, a well-known androgen-regulated transcription factor (64, 65), synergistically promotes prostate carcinogenesis (66).
Androgen-induced proliferation and survival of androgen-sensitive LNCaP cells depend on the activation of PI3K/AKT. Inhibition of AKT with a dominant-negative AKT or a PI3K inhibitor significantly attenuates androgen-induced cell proliferation (4, 5). Androgen-induced AKT activation requires the AR, but deletion of the ligand-binding domain of AR does not abolish it, indicating that this regulation is independent of AR transcriptional activity. Indeed, androgen-bound AR physically binds to the p85α regulatory subunit of PI3K and thereby activates PI3K/AKT (4, 5). This is truly a two-way crosstalk, since AR expression and activity are also regulated by PI3K/AKT (67–69). Additional details about the crosstalk between androgen/AR and PI3K/AKT pathways have previously been discussed in several other reviews (61, 70).
The cell cycle, which is governed by the coordination of cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors, becomes deregulated in prostate cancer. Androgen/AR signaling is critical for normal prostate cell cycle progression, and dysregulation of this signaling may contribute to prostate cancer progression. Multiple mechanisms have been attributed to the effects of androgens on the cell cycle (71). For instance, androgens are important for cyclin D expression. Androgen-deprived prostate cancer cells arrest in early G1 phase, concomitant with loss of cyclin D, reduced CDK4 activity, and activated Rb. Addition of androgen rapidly increases cyclin D expression and promotes cell cycle progression (72, 73). Androgens increase cyclin D1 and D2 expression at the protein level but not at the mRNA level, suggesting that this regulation is at a post-transcriptional level. Androgen-induced cyclin D expression depends on activation of mammalian target of rapamycin (mTOR), which enhances the translation of cyclin D1 mRNA (73, 74). Although mTOR is a well-known target of AKT, androgen-induced mTOR activation is not mediated by AKT (73). The mechanism by which androgens activate mTOR remains unknown.
Androgens also regulate cell cycle progression through the CDK inhibitor p21Waf1/Cip1. Androgens positively regulate p21Waf1/Cip1 expression through an ARE within its promoter (75). Induction of p21Waf1/Cip1 by androgens may promote the assembly of active cyclin D1/CDK4 or CDK6 complexes (71, 76). In contrast to the upregulation of p21Waf1/Cip1, androgen treatment downregulates the expression of another CDK inhibitor p27kip1, resulting in inhibition of cyclin E/CDK2 activity (77). This androgen-induced reduction of p27Kip1 is mediated by decreased expression of the F-box protein SKP2 (78) which controls the ubiquitin-dependent degradation of p27Kip1 (79, 80).
4 Androgen Action on Prostate Cell Apoptosis/ Survival
Androgens are essential for the survival of both normal and malignant prostate epithelium (21). Androgen withdrawal in adult rodents and humans induces apoptosis in the secretory epithelium (81, 82). Because most human prostate cancers are initially androgen responsive, androgen deprivation therapy remains the standard treatment for advanced prostate cancer. Recent data have revealed important pathways through which androgens regulate prostate cell apoptosis (83, 84).
Two types of signaling pathways lead to cell apoptosis: intrinsic or extrinsic. The intrinsic pathway is initiated by a variety of cell stresses, which lead to changes in mitochondrial permeability and release of cytochrome C and Smac/DIABLO. Antiapoptotic members of the BH3 family such as Bcl-2 and Bcl-XL inhibit intrinsic apoptosis by preventing the leakage of cytochrome C and Smac/DIABLO from mitochondria. Elevated Bcl-2 expression is implicated in a variety of human malignancies, including prostate cancer (85, 86). Whereas Bcl-2 expression is positive in most CRPCs, only approximately 30% androgen-dependent prostate cancers express low levels of Bcl-2, suggesting that Bcl-2 may contribute to the development of CRPC (87–89). It has been shown that androgens suppress Bcl-2 expression but the underlying mechanism is still unclear. Huang et al. reported that the regulation of Bcl-2 by androgens might be an indirect effect of AR activation, probably mediated by the E2F1 protein through a putative E2F-binding site in the promoter of the Bcl-2 gene (90).
Bak1 is another member of the BH3 family, which is also known to be regulated by androgens (91). Unlike Bcl-2, Bak1 is a proapoptotic protein. Under normal circumstances, Bak1 forms a complex with Bcl-2 or Mcl-1, which restrains Bak1 activation. Elimination of Bcl-2 or Mcl-1 caused by an apoptotic stimulus, such as DNA damage, releases Bak1 from this inhibitory complex and promotes apoptosis (92). Bak-1 expression has been associated with prostate cancer progression. Bak1 is expressed in approximately 75% of primary and untreated localized prostate cancers, but in only approximately 33% of CRPCs (89). The suppression of Bak1 expression by androgens is mediated by a microRNA. MicroRNAs are a class of naturally occurring small RNAs, which do not encode proteins but regulate the expression of other genes. Androgens transcriptionally upregulate miR-125b, which then represses Bak1 expression (91). Thus, androgens suppress the expression of both Bcl-2 and Bak1 via different mechanisms. Further studies are essential to determine whether these androgen actions contribute to prostate carcinogenesis and cancer progression.
The extrinsic apoptotic pathway is mediated by death receptor signaling, which is triggered by ligands such as TNF-α, TRAIL, and FasL. Normal prostate cells are highly resistant to death receptor-induced cell apoptosis due to activation of NF-κB, which promotes cell proliferation and inhibits apoptosis (93). It has been reported that androgens inhibit TNF-α-induced NF-κB activation via multiple mechanisms (94–96) (Fig. 2.2). Keller et al. showed that androgens prevent the degradation of IκBα, which binds to NF-κB and inhibits its activation (95). AR activation also results in a decrease in RelA/p65, a subunit of NF-κB, thereby reducing its nuclear localization and transcriptional activity (97). Another mechanism whereby androgens affect NF-κB activity is through the formation of an AR-p65 complex via CREB-binding protein (CBP), which inhibits both p65 and AR transcriptional activities (94).
Androgen action on TNF-α-induced signaling pathways. TNF-α binding to trimeric TNFR1 leads to assembly of complex I, which then results in activation of NF-κB, JNK, and/or the caspase cascade, depending on cellular context. All of these three TNF-α downstream signaling pathways can be regulated by androgen–AR via different mechanisms, as summarized in the text. Dashed line indicates that the underlying mechanism is not fully elucidated.
C-FLIP is a caspase-8 homologue, which functions as a dominant inhibitor of caspase-8 (98), thereby negatively regulating death receptor-induced apoptosis. In prostate cancer cells, increased c-FLIP expression is associated with increased resistance to death receptor-induced apoptosis (99, 100). LNCaP xenografts overexpressing c-FLIP are also resistant to castration-induced growth inhibition, suggesting a role of c-FLIP in the development of CRPC (99). It has also been observed that both c-FLIP mRNA and protein levels are reduced during progression to CRPC in animal models (101, 102). C-FLIP is directly regulated by androgens via a cluster of four AREs within a 156-bp region downstream from the transcription start site (99). Accordingly, both c-FLIP mRNA and protein levels are reduced following castration of rats in multiple tissues, including dorsolateral prostate and seminal vesicles (100). Unexpectedly, it has also been reported that androgen treatment downregulates c-FLIP in LNCaP cells, in which AKT is constitutively activated due to loss of PTEN. This discrepancy might be explained by the involvement of an AKT-regulated transcription factor, FOXO3a. Androgen induction of c-FLIP requires the presence of FOXO3a, which binds to the AR and potentially to the Forkhead-binding site within the c-FLIP promoter (102). Expression of FOXO3a TM, a constitutively active form of FOXO3a, rescues the androgen induction of c-FLIP in LNCaP cells, supporting a critical role of FOXO3a in androgen-induced c-FLIP upregulation (102).
FOXO3a belongs to the Forkhead transcription factor class-O family, members of which can act as tumor suppressors in a variety of malignancies (103, 104). Other members of the FOXO family include FOXO1, FOXO4, and FOXO6. AKT is a major regulator of the FOXO proteins. AKT phosphorylates the FOXO proteins, leading to their retention in the cytoplasm and proteasome-mediated degradation (105, 106) (Fig. 2.1). FOXO proteins inhibit cell proliferation and induce apoptosis in prostate cells. Thus, their activities are hypothesized to be reduced during prostate cancer progression (107, 108). Androgens negatively regulate the proapoptotic effects of FOXO1 through a physical interaction with it. Liganded AR blocks the DNA-binding activity of FOXO1 and impairs the ability of FOXO1 to induce Fas ligand expression and prostate cancer cell apoptosis (109). Moreover, androgen treatment results in a reduction of FOXO1 expression at the protein level via a proteolytic mechanism. Treatment of LNCaP cells with androgens leads to FOXO1 protein cleavage and produces a truncated FOXO1, which lacks ∼120 amino acid residues in the C-terminus. Ectopic expression of this truncated FOXO1 inhibits the transcriptional activity of the intact FOXO1, suggesting that androgen-induced FOXO1 protein cleavage results in reduction of FOXO1 transcriptional activity (107).
TRADD (TNF receptor-associated death domain), which is a transducer for death receptor-induced signaling, is also a target of androgens (110). TRADD mediates TNFR1-induced apoptosis as well as NF-κB activation (111). Overexpression of TRADD in a variety of cell lines leads to apoptosis; however, knockdown or knockout of TRADD expression in some cell lines does not inhibit apoptosis, suggesting that its function depends on the cellular context (112–114). TRADD protein is reduced in CRPC cells compared to androgen-responsive cells. Androgen deprivation reduces TRADD expression in prostate cancer cell lines, xenografts, and human tissues. Moreover, androgen treatment increases TRADD expression at both the mRNA and protein levels (110). Unpublished data (D. Wang, personal communication) suggest that this regulation is an indirect action of androgens because it requires AR and de novo protein synthesis. Reduced TRADD expression may account for the reduced sensitivity of CRPC cells to TNF-α.
5 Androgen Action on Prostate Cancer Metastasis
A pivotal problem of prostate cancer, as in other cancers, is its propensity to metastasize. The process of tumor metastasis includes the following: activation of epithelial–mesenchymal transition (EMT), remodeling of the extracellular matrix, neovascularization, and migration to specific secondary sites. Many of the androgen-regulated signaling pathways that were discussed above are also important for prostate cancer metastasis. For instance, NF-κB activity has been associated with many types of metastases. Inhibition of NF-κB activity in metastatic prostate cancer is associated with reduced expression of vascular endothelial growth factor, interleukin-8, and matrix metalloproteinase-9 and a concomitant decrease in angiogenesis, invasion, and metastasis in nude mice (115). Furthermore, nuclear NF-κB expression in primary prostate cancers is highly predictive for pelvic lymph node metastases (116). Thus, the regulation of prostate cancer metastasis by androgens may be achieved by crosstalk between androgen and NF-κB signaling pathways.
Cell adhesion molecules such as cadherins play a critical role in the activation of EMT (117). Cadherins are a class of type-1 transmembrane glycoproteins, of which E-cadherin and N-cadherin are the best characterized in prostate cancers. E-cadherin is an important tumor suppressor gene. Loss of E-cadherin expression disrupts cell–cell junctions and consequently promotes cell migration, leading to tumor metastasis. Multiple studies reported that loss of E-cadherin expression enhances the progression from nonmetastatic to metastatic carcinoma (118, 119). In primary prostate cancers, reduced E-cadherin expression has been correlated with increased tumor grade, bone metastasis, and poor prognosis (120, 121). In contrast, increased levels of N-cadherin and cadherin-11 are associated with poorly differentiated and metastatic prostate cancers (122, 123). In more aggressive prostate cancer specimens, N-cadherin expression is increased while E-cadherin is reduced. This phenomenon is called ‘cadherin switching’ (124). Interestingly, both E-cadherin and N-cadherin appear to be regulated by androgens (125, 126). Androgen deprivation therapy leads to elevated expression of E-cadherin in prostate cancer, suggesting that androgens repress E-cadherin expression (127). Moreover, androgen treatment reduces E-cadherin expression in the breast cancer cell lines MCF7 and T47D. Identification of AREs within the promoter of the E-cadherin gene further suggests that this repression is a direct transcriptional effect of AR (125). However, because these studies were not conducted in prostate cancer cell lines or models, it is still not clear whether similar mechanisms apply to prostate cancer cells. More studies are needed to elucidate the role of androgens on E-cadherin expression and function in prostate cancer.
In contrast to E-cadherin, N-cadherin is induced by androgen deprivation in experimental castration-recurrent prostate cancer models as well as in human prostate tumors (126). It has also been shown that testosterone increases N-cadherin expression in motor neurons (128). Taken together, these results suggest that androgens may positively regulate the expression of N-cadherin.
Cadherin-11 is a homophilic cell adhesion molecule that mediates osteoblast adhesion and thereby plays a critical role in the metastasis of prostate cancer to bone. Increased cadherin-11 expression correlates with development of CRPC (129). Cadherin-11 appears to be indirectly regulated by androgens, suggesting a role of androgen in the metastasis of prostate cancer to bone (130).
Maspin is a serine protease inhibitor with tumor suppressing properties. Loss of maspin is associated with a variety of tumors, such as breast and prostate cancers (131, 132). Consistently, re-expression of maspin in prostate cancer cells inhibits tumor growth and prostate cancer-induced bone remodeling (133). Maspin exerts its anti-metastasis activities via multiple mechanisms. For instance, maspin blocks FGF and vascular endothelial growth factor-mediated endothelial cell migration in vitro. Maspin also inhibits prostate cancer growth and tumor angiogenesis in vivo, probably mediated by its ability to inhibit the degradation of extracellular matrix via tPA and pro-uPA (134–136). Maspin expression increases in prostate cancer cells and tissues following androgen deprivation while androgen treatment decreases maspin expression (132, 137). Identification of an ARE element in the promoter of the maspin gene has confirmed this regulation as a direct transcriptional effect of the androgen receptor (137). Therefore, androgens may affect prostate cancer progression and metastasis via regulation of maspin expression.
6 Conclusions
It has long been recognized that androgens play a critical role in prostate carcinogenesis. In this review we have highlighted several androgen-regulated signaling pathways and factors that may be involved in prostate carcinogenesis (Table 2.1). Although under certain circumstances androgens may inhibit cell proliferation or promote cell death, in general, it is well accepted that androgens are critical for prostate cancer cell proliferation and survival. However, the effects of androgens are diverse and complex, and focusing on one or two signaling pathways for delineating mechanisms is likely to be an oversimplification. More importantly, the downstream signaling pathways of androgen may also crosstalk with each other, making the contributions of androgen to prostate carcinogenesis more complicated. Nonetheless, recent development of more potent antiandrogens and inhibitors of androgen metabolism, which are in clinical trials (138–140), will aid in understanding the role of androgen signaling in prostate cancer cells. Taken together, better understanding of AR action is likely to lead to better clinical treatments for prostate cancer.
References
Attar, R. M., Takimoto, C. H., and Gottardis, M. M. (2009) Castration-resistant prostate cancer: locking up the molecular escape routes, Clin Cancer Res 15, 3251–3255.
Evans, R. M. (1988) The steroid and thyroid hormone receptor superfamily, Science 240, 889–895.
Dehm, S. M., and Tindall, D. J. (2006) Molecular regulation of androgen action in prostate cancer, J Cell Biochem 99, 333–344.
Sun, M., Yang, L., Feldman, R. I., Sun, X. M., Bhalla, K. N., Jove, R., Nicosia, S. V., and Cheng, J. Q. (2003) Activation of phosphatidylinositol 3-kinase/Akt pathway by androgen through interaction of p85alpha, androgen receptor, and Src, J Biol Chem 278, 42992–43000.
Baron, S., Manin, M., Beaudoin, C., Leotoing, L., Communal, Y., Veyssiere, G., and Morel, L. (2004) Androgen receptor mediates non-genomic activation of phosphatidylinositol 3-OH kinase in androgen-sensitive epithelial cells, J Biol Chem 279, 14579–14586.
Sheflin, L. G., Zou, A. P., and Spaulding, S. W. (2004) Androgens regulate the binding of endogenous HuR to the AU-rich 3’UTRs of HIF-1alpha and EGF mRNA, Biochem Biophys Res Commun 322, 644–651.
Foradori, C. D., Weiser, M. J., and Handa, R. J. (2008) Non-genomic actions of androgens, Front Neuroendocrinol 29, 169–181.
Kousteni, S., Bellido, T., Plotkin, L. I., O’Brien, C. A., Bodenner, D. L., Han, L., Han, K., DiGregorio, G. B., Katzenellenbogen, J. A., Katzenellenbogen, B. S., Roberson, P. K., Weinstein, R. S., Jilka, R. L., and Manolagas, S. C. (2001) Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity, Cell 104, 719–730.
Kampa, M., Papakonstanti, E. A., Hatzoglou, A., Stathopoulos, E. N., Stournaras, C., and Castanas, E. (2002) The human prostate cancer cell line LNCaP bears functional membrane testosterone receptors that increase PSA secretion and modify actin cytoskeleton, FASEB J 16, 1429–1431.
Jemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J., and Thun, M. J. (2009) Cancer statistics, 2009, CA Cancer J Clin 59, 225–249.
Jemal, A., Thun, M. J., Ries, L. A., Howe, H. L., Weir, H. K., Center, M. M., Ward, E., Wu, X. C., Eheman, C., Anderson, R., Ajani, U. A., Kohler, B., and Edwards, B. K. (2008) Annual report to the nation on the status of cancer, 1975–2005, featuring trends in lung cancer, tobacco use, and tobacco control, J Natl Cancer Inst 100, 1672–1694.
De Marzo, A. M., DeWeese, T. L., Platz, E. A., Meeker, A. K., Nakayama, M., Epstein, J. I., Isaacs, W. B., and Nelson, W. G. (2004) Pathological and molecular mechanisms of prostate carcinogenesis: implications for diagnosis, detection, prevention, and treatment, J Cell Biochem 91, 459–477.
Ramsay, A. K., and Leung, H. Y. (2009) Signalling pathways in prostate carcinogenesis: potentials for molecular-targeted therapy, Clin Sci (Lond) 117, 209–228.
Huggins, C. (1967) Endocrine-induced regression of cancers, Cancer Res 27, 1925–1930.
Huggins, C., and Hodges, C. V. (1972) Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate, CA Cancer J Clin 22, 232–240.
Isbarn, H., Pinthus, J. H., Marks, L. S., Montorsi, F., Morales, A., Morgentaler, A., and Schulman, C. (2009) Testosterone and prostate cancer: revisiting old paradigms, Eur Urol 56, 48–56.
Morgentaler, A. (2006) Testosterone and prostate cancer: an historical perspective on a modern myth, Eur Urol 50, 935–939.
Morgentaler, A., and Traish, A. M. (2009) Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth, Eur Urol 55, 310–320.
Debes, J. D., and Tindall, D. J. (2004) Mechanisms of androgen-refractory prostate cancer, N Engl J Med 351, 1488–1490.
Dehm, S. M., and Tindall, D. J. (2006) Ligand-independent androgen receptor activity is activation function-2-independent and resistant to antiandrogens in androgen refractory prostate cancer cells, J Biol Chem 281, 27882–27893.
Dehm, S. M., and Tindall, D. J. (2005) Regulation of androgen receptor signaling in prostate cancer, Expert Rev Anticancer Ther 5, 63–74.
Dehm, S. M., and Tindall, D. J. (2007) Androgen receptor structural and functional elements: role and regulation in prostate cancer, Mol Endocrinol 21, 2855–2863.
Hsing, A. W. (2001) Hormones and prostate cancer: what’s next? Epidemiol Rev 23, 42–58.
Tomlins, S. A., Rhodes, D. R., Perner, S., Dhanasekaran, S. M., Mehra, R., Sun, X. W., Varambally, S., Cao, X., Tchinda, J., Kuefer, R., Lee, C., Montie, J. E., Shah, R. B., Pienta, K. J., Rubin, M. A., and Chinnaiyan, A. M. (2005) Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer, Science 310, 644–648.
Hsu, T., Trojanowska, M., and Watson, D. K. (2004) Ets proteins in biological control and cancer, J Cell Biochem 91, 896–903.
Hermans, K. G., van Marion, R., van Dekken, H., Jenster, G., van Weerden, W. M., and Trapman, J. (2006) TMPRSS2:ERG fusion by translocation or interstitial deletion is highly relevant in androgen-dependent prostate cancer, but is bypassed in late-stage androgen receptor-negative prostate cancer, Cancer Res 66, 10658–10663.
Soller, M. J., Isaksson, M., Elfving, P., Soller, W., Lundgren, R., and Panagopoulos, I. (2006) Confirmation of the high frequency of the TMPRSS2/ERG fusion gene in prostate cancer, Genes Chromosomes Cancer 45, 717–719.
Rajput, A. B., Miller, M. A., De Luca, A., Boyd, N., Leung, S., Hurtado-Coll, A., Fazli, L., Jones, E. C., Palmer, J. B., Gleave, M. E., Cox, M. E., and Huntsman, D. G. (2007) Frequency of the TMPRSS2:ERG gene fusion is increased in moderate to poorly differentiated prostate cancers, J Clin Pathol 60, 1238–1243.
Lin, B., Ferguson, C., White, J. T., Wang, S., Vessella, R., True, L. D., Hood, L., and Nelson, P. S. (1999) Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2, Cancer Res 59, 4180–4184.
Vaarala, M. H., Porvari, K., Kyllonen, A., Lukkarinen, O., and Vihko, P. (2001) The TMPRSS2 gene encoding transmembrane serine protease is overexpressed in a majority of prostate cancer patients: detection of mutated TMPRSS2 form in a case of aggressive disease, Int J Cancer 94, 705–710.
Afar, D. E., Vivanco, I., Hubert, R. S., Kuo, J., Chen, E., Saffran, D. C., Raitano, A. B., and Jakobovits, A. (2001) Catalytic cleavage of the androgen-regulated TMPRSS2 protease results in its secretion by prostate and prostate cancer epithelia, Cancer Res 61, 1686–1692.
Vaarala, M. H., Porvari, K. S., Kellokumpu, S., Kyllonen, A. P., and Vihko, P. T. (2001) Expression of transmembrane serine protease TMPRSS2 in mouse and human tissues, J Pathol 193, 134–140.
Petrovics, G., Liu, A., Shaheduzzaman, S., Furusato, B., Sun, C., Chen, Y., Nau, M., Ravindranath, L., Chen, Y., Dobi, A., Srikantan, V., Sesterhenn, I. A., McLeod, D. G., Vahey, M., Moul, J. W., and Srivastava, S. (2005) Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome, Oncogene 24, 3847–3852.
Lin, C., Yang, L., Tanasa, B., Hutt, K., Ju, B. G., Ohgi, K., Zhang, J., Rose, D. W., Fu, X. D., Glass, C. K., and Rosenfeld, M. G. (2009) Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer, Cell 139, 1069–1083.
Kaaks, R., Lukanova, A., and Sommersberg, B. (2000) Plasma androgens, IGF-1, body size, and prostate cancer risk: a synthetic review, Prostate Cancer Prostatic Dis 3, 157–172.
Kwabi-Addo, B., Ozen, M., and Ittmann, M. (2004) The role of fibroblast growth factors and their receptors in prostate cancer, Endocr Relat Cancer 11, 709–724.
Byrne, R. L., Leung, H., and Neal, D. E. (1996) Peptide growth factors in the prostate as mediators of stromal epithelial interaction, Br J Urol 77, 627–633.
Wu, Y., Zhao, W., Zhao, J., Pan, J., Wu, Q., Zhang, Y., Bauman, W. A., and Cardozo, C. P. (2007) Identification of androgen response elements in the insulin-like growth factor I upstream promoter, Endocrinology 148, 2984–2993.
Pandini, G., Mineo, R., Frasca, F., Roberts, C. T., Jr., Marcelli, M., Vigneri, R., and Belfiore, A. (2005) Androgens up-regulate the insulin-like growth factor-I receptor in prostate cancer cells, Cancer Res 65, 1849–1857.
Yoshizawa, A., and Ogikubo, S. (2006) IGF binding protein-5 synthesis is regulated by testosterone through transcriptional mechanisms in androgen responsive cells, Endocr J 53, 811–818.
Kojima, S., Mulholland, D. J., Ettinger, S., Fazli, L., Nelson, C. C., and Gleave, M. E. (2006) Differential regulation of IGFBP-3 by the androgen receptor in the lineage-related androgen-dependent LNCaP and androgen-independent C4-2 prostate cancer models, Prostate 66, 971–986.
Le, H., Arnold, J. T., McFann, K. K., and Blackman, M. R. (2006) DHT and testosterone, but not DHEA or E2, differentially modulate IGF-I, IGFBP-2, and IGFBP-3 in human prostatic stromal cells, Am J Physiol Endocrinol Metab 290, E952–960.
Peng, L., Wang, J., Malloy, P. J., and Feldman, D. (2008) The role of insulin-like growth factor binding protein-3 in the growth inhibitory actions of androgens in LNCaP human prostate cancer cells, Int J Cancer 122, 558–566.
Tanaka, A., Miyamoto, K., Minamino, N., Takeda, M., Sato, B., Matsuo, H., and Matsumoto, K. (1992) Cloning and characterization of an androgen-induced growth factor essential for the androgen-dependent growth of mouse mammary carcinoma cells, Proc Natl Acad Sci USA 89, 8928–8932.
Rudra-Ganguly, N., Zheng, J., Hoang, A. T., and Roy-Burman, P. (1998) Downregulation of human FGF8 activity by antisense constructs in murine fibroblastic and human prostatic carcinoma cell systems, Oncogene 16, 1487–1492.
Daphna-Iken, D., Shankar, D. B., Lawshe, A., Ornitz, D. M., Shackleford, G. M., and MacArthur, C. A. (1998) MMTV-Fgf8 transgenic mice develop mammary and salivary gland neoplasia and ovarian stromal hyperplasia, Oncogene 17, 2711–2717.
Tanaka, A., Furuya, A., Yamasaki, M., Hanai, N., Kuriki, K., Kamiakito, T., Kobayashi, Y., Yoshida, H., Koike, M., and Fukayama, M. (1998) High frequency of fibroblast growth factor (FGF) 8 expression in clinical prostate cancers and breast tissues, immunohistochemically demonstrated by a newly established neutralizing monoclonal antibody against FGF 8, Cancer Res 58, 2053–2056.
Dorkin, T. J., Robinson, M. C., Marsh, C., Bjartell, A., Neal, D. E., and Leung, H. Y. (1999) FGF8 over-expression in prostate cancer is associated with decreased patient survival and persists in androgen independent disease, Oncogene 18, 2755–2761.
Gnanapragasam, V. J., Robson, C. N., Neal, D. E., and Leung, H. Y. (2002) Regulation of FGF8 expression by the androgen receptor in human prostate cancer, Oncogene 21, 5069–5080.
Sherwood, E. R., and Lee, C. (1995) Epidermal growth factor-related peptides and the epidermal growth factor receptor in normal and malignant prostate, World J Urol 13, 290–296.
Li, Z., Szabolcs, M., Terwilliger, J. D., and Efstratiadis, A. (2006) Prostatic intraepithelial neoplasia and adenocarcinoma in mice expressing a probasin-Neu oncogenic transgene, Carcinogenesis 27, 1054–1067.
Torring, N., Dagnaes-Hansen, F., Sorensen, B. S., Nexo, E., and Hynes, N. E. (2003) ErbB1 and prostate cancer: ErbB1 activity is essential for androgen-induced proliferation and protection from the apoptotic effects of LY294002, Prostate 56, 142–149.
Pignon, J. C., Koopmansch, B., Nolens, G., Delacroix, L., Waltregny, D., and Winkler, R. (2009) Androgen receptor controls EGFR and ERBB2 gene expression at different levels in prostate cancer cell lines, Cancer Res 69, 2941–2949.
Dehm, S. M., Schmidt, L. J., Heemers, H. V., Vessella, R. L., and Tindall, D. J. (2008) Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance, Cancer Res 68, 5469–5477.
Libertini, S. J., Tepper, C. G., Rodriguez, V., Asmuth, D. M., Kung, H. J., and Mudryj, M. (2007) Evidence for calpain-mediated androgen receptor cleavage as a mechanism for androgen independence, Cancer Res 67, 9001–9005.
Yuan, T. L., and Cantley, L. C. (2008) PI3K pathway alterations in cancer: variations on a theme, Oncogene 27, 5497–5510.
Vivanco, I., and Sawyers, C. L. (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer, Nat Rev Cancer 2, 489–501.
Yoshimoto, M., Cunha, I. W., Coudry, R. A., Fonseca, F. P., Torres, C. H., Soares, F. A., and Squire, J. A. (2007) FISH analysis of 107 prostate cancers shows that PTEN genomic deletion is associated with poor clinical outcome, Br J Cancer 97, 678–685.
Suzuki, H., Freije, D., Nusskern, D. R., Okami, K., Cairns, P., Sidransky, D., Isaacs, W. B., and Bova, G. S. (1998) Interfocal heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic prostate cancer tissues, Cancer Res 58, 204–209.
Verhagen, P. C., van Duijn, P. W., Hermans, K. G., Looijenga, L. H., van Gurp, R. J., Stoop, H., van der Kwast, T. H., and Trapman, J. (2006) The PTEN gene in locally progressive prostate cancer is preferentially inactivated by bi-allelic gene deletion, J Pathol 208, 699–707.
Sarker, D., Reid, A. H., Yap, T. A., and de Bono, J. S. (2009) Targeting the PI3K/AKT pathway for the treatment of prostate cancer, Clin Cancer Res 15, 4799–4805.
Murillo, H., Huang, H., Schmidt, L. J., Smith, D. I., and Tindall, D. J. (2001) Role of PI3K signaling in survival and progression of LNCaP prostate cancer cells to the androgen refractory state, Endocrinology 142, 4795–4805.
Trotman, L. C., Niki, M., Dotan, Z. A., Koutcher, J. A., Di Cristofano, A., Xiao, A., Khoo, A. S., Roy-Burman, P., Greenberg, N. M., Van Dyke, T., Cordon-Cardo, C., and Pandolfi, P. P. (2003) Pten dose dictates cancer progression in the prostate, PLoS Biol 1, E59.
He, W. W., Sciavolino, P. J., Wing, J., Augustus, M., Hudson, P., Meissner, P. S., Curtis, R. T., Shell, B. K., Bostwick, D. G., Tindall, D. J., Gelmann, E. P., Abate-Shen, C., and Carter, K. C. (1997) A novel human prostate-specific, androgen-regulated homeobox gene (NKX3.1) that maps to 8p21, a region frequently deleted in prostate cancer, Genomics 43, 69–77.
Prescott, J. L., Blok, L., and Tindall, D. J. (1998) Isolation and androgen regulation of the human homeobox cDNA, NKX3.1, Prostate 35, 71–80.
Kim, M. J., Cardiff, R. D., Desai, N., Banach-Petrosky, W. A., Parsons, R., Shen, M. M., and Abate-Shen, C. (2002) Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis, Proc Natl Acad Sci USA 99, 2884–2889.
Lin, H. K., Yeh, S., Kang, H. Y., and Chang, C. (2001) Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor, Proc Natl Acad Sci USA 98, 7200–7205.
Lin, H. K., Hu, Y. C., Yang, L., Altuwaijri, S., Chen, Y. T., Kang, H. Y., and Chang, C. (2003) Suppression versus induction of androgen receptor functions by the phosphatidylinositol 3-kinase/Akt pathway in prostate cancer LNCaP cells with different passage numbers, J Biol Chem 278, 50902–50907.
Taneja, S. S., Ha, S., Swenson, N. K., Huang, H. Y., Lee, P., Melamed, J., Shapiro, E., Garabedian, M. J., and Logan, S. K. (2005) Cell-specific regulation of androgen receptor phosphorylation in vivo, J Biol Chem 28 0, 40916–40924.
Wang, Y., Kreisberg, J. I., and Ghosh, P. M. (2007) Cross-talk between the androgen receptor and the phosphatidylinositol 3-kinase/Akt pathway in prostate cancer, Curr Cancer Drug Targets 7, 591–604.
Balk, S. P., and Knudsen, K. E. (2008) AR, the cell cycle, and prostate cancer, Nucl Recept Signal 6, e001.
Knudsen, K. E., Arden, K. C., and Cavenee, W. K. (1998) Multiple G1 regulatory elements control the androgen-dependent proliferation of prostatic carcinoma cells, J Biol Chem 273, 20213–20222.
Xu, Y., Chen, S. Y., Ross, K. N., and Balk, S. P. (2006) Androgens induce prostate cancer cell proliferation through mammalian target of rapamycin activation and post-transcriptional increases in cyclin D proteins, Cancer Res 66, 7783–7792.
Gera, J. F., Mellinghoff, I. K., Shi, Y., Rettig, M. B., Tran, C., Hsu, J. H., Sawyers, C. L., and Lichtenstein, A. K. (2004) AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression, J Biol Chem 279, 2737–2746.
Lu, S., Liu, M., Epner, D. E., Tsai, S. Y., and Tsai, M. J. (1999) Androgen regulation of the cyclin-dependent kinase inhibitor p21 gene through an androgen response element in the proximal promoter, Mol Endocrinol 13, 376–384.
Chen, Y., Robles, A. I., Martinez, L. A., Liu, F., Gimenez-Conti, I. B., and Conti, C. J. (1996) Expression of G1 cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors in androgen-induced prostate proliferation in castrated rats, Cell Growth Differ 7, 1571–1578.
Ye, D., Mendelsohn, J., and Fan, Z. (1999) Androgen and epidermal growth factor down-regulate cyclin-dependent kinase inhibitor p27Kip1 and costimulate proliferation of MDA PCa 2a and MDA PCa 2b prostate cancer cells, Clin Cancer Res 5, 2171–2177.
Lu, L., Schulz, H., and Wolf, D. A. (2002) The F-box protein SKP2 mediates androgen control of p27 stability in LNCaP human prostate cancer cells, BMC Cell Biol 3, 22.
Nakayama, K., Nagahama, H., Minamishima, Y. A., Matsumoto, M., Nakamichi, I., Kitagawa, K., Shirane, M., Tsunematsu, R., Tsukiyama, T., Ishida, N., Kitagawa, M., Nakayama, K., and Hatakeyama, S. (2000) Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication, EMBO J 19, 2069–2081.
Xu, K., Belunis, C., Chu, W., Weber, D., Podlaski, F., Huang, K. S., Reed, S. I., and Vassilev, L. T. (2003) Protein-protein interactions involved in the recognition of p27 by E3 ubiquitin ligase, Biochem J 371, 957–964.
Kyprianou, N., and Isaacs, J. T. (1988) Activation of programmed cell death in the rat ventral prostate after castration, Endocrinology 122, 552–562.
Buttyan, R., Shabsigh, A., Perlman, H., and Colombel, M. (1999) Regulation of Apoptosis in the Prostate Gland by Androgenic Steroids, Trends Endocrinol Metab 10, 47–54.
Kimura, K., Markowski, M., Bowen, C., and Gelmann, E. P. (2001) Androgen blocks apoptosis of hormone-dependent prostate cancer cells, Cancer Res 61, 5611–5618.
Guseva, N. V., Taghiyev, A. F., Rokhlin, O. W., and Cohen, M. B. (2004) Death receptor-induced cell death in prostate cancer, J Cell Biochem 91, 70–99.
Raffo, A. J., Perlman, H., Chen, M. W., Day, M. L., Streitman, J. S., and Buttyan, R. (1995) Overexpression of bcl-2 protects prostate cancer cells from apoptosis in vitro and confers resistance to androgen depletion in vivo, Cancer Res 55, 4438–4445.
Bruckheimer, E. M., Brisbay, S., Johnson, D. J., Gingrich, J. R., Greenberg, N., and McDonnell, T. J. (2000) Bcl-2 accelerates multistep prostate carcinogenesis in vivo, Oncogene 19, 5251–5258.
McDonnell, T. J., Troncoso, P., Brisbay, S. M., Logothetis, C., Chung, L. W., Hsieh, J. T., Tu, S. M., and Campbell, M. L. (1992) Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer, Cancer Res 52, 6940–6944.
Colombel, M., Symmans, F., Gil, S., O’Toole, K. M., Chopin, D., Benson, M., Olsson, C. A., Korsmeyer, S., and Buttyan, R. (1993) Detection of the apoptosis-suppressing oncoprotein bc1-2 in hormone-refractory human prostate cancers, Am J Pathol 143, 390–400.
Yoshino, T., Shiina, H., Urakami, S., Kikuno, N., Yoneda, T., Shigeno, K., and Igawa, M. (2006) Bcl-2 expression as a predictive marker of hormone-refractory prostate cancer treated with taxane-based chemotherapy, Clin Cancer Res 12, 6116–6124.
Huang, H., Zegarra-Moro, O. L., Benson, D., and Tindall, D. J. (2004) Androgens repress Bcl-2 expression via activation of the retinoblastoma (RB) protein in prostate cancer cells, Oncogene 23, 2161–2176.
Shi, X. B., Xue, L., Yang, J., Ma, A. H., Zhao, J., Xu, M., Tepper, C. G., Evans, C. P., Kung, H. J., and deVere White, R. W. (2007) An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells, Proc Natl Acad Sci USA 104, 19983–19988.
Cuconati, A., Mukherjee, C., Perez, D., and White, E. (2003) DNA damage response and MCL-1 destruction initiate apoptosis in adenovirus-infected cells, Genes Dev 17, 2922–2932.
Van Antwerp, D. J., Martin, S. J., Kafri, T., Green, D. R., and Verma, I. M. (1996) Suppression of TNF-alpha-induced apoptosis by NF-kappaB, Science 274, 787–789.
Palvimo, J. J., Reinikainen, P., Ikonen, T., Kallio, P. J., Moilanen, A., and Janne, O. A. (1996) Mutual transcriptional interference between RelA and androgen receptor, J Biol Chem 271, 24151–24156.
Keller, E. T., Chang, C., and Ershler, W. B. (1996) Inhibition of NFkappaB activity through maintenance of IkappaBalpha levels contributes to dihydrotestosterone-mediated repression of the interleukin-6 promoter, J Biol Chem 271, 26267–26275.
Norata, G. D., Tibolla, G., Seccomandi, P. M., Poletti, A., and Catapano, A. L. (2006) Dihydrotestosterone decreases tumor necrosis factor-alpha and lipopolysaccharide-induced inflammatory response in human endothelial cells, J Clin Endocrinol Metab 91, 546–554.
Nelius, T., Filleur, S., Yemelyanov, A., Budunova, I., Shroff, E., Mirochnik, Y., Aurora, A., Veliceasa, D., Xiao, W., Wang, Z., and Volpert, O. V. (2007) Androgen receptor targets NFkappaB and TSP1 to suppress prostate tumor growth in vivo, Int J Cancer 121, 999–1008.
Kreuz, S., Siegmund, D., Scheurich, P., and Wajant, H. (2001) NF-kappaB inducers upregulate cFLIP, a cycloheximide-sensitive inhibitor of death receptor signaling, Mol Cell Biol 21, 3964–3973.
Gao, S., Lee, P., Wang, H., Gerald, W., Adler, M., Zhang, L., Wang, Y. F., and Wang, Z. (2005) The androgen receptor directly targets the cellular Fas/FasL-associated death domain protein-like inhibitory protein gene to promote the androgen-independent growth of prostate cancer cells, Mol Endocrinol 19, 1792–1802.
Raclaw, K. A., Heemers, H. V., Kidd, E. M., Dehm, S. M., and Tindall, D. J. (2008) Induction of FLIP expression by androgens protects prostate cancer cells from TRAIL-mediated apoptosis, Prostate 68, 1696–1706.
Gao, S., Wang, H., Lee, P., Melamed, J., Li, C. X., Zhang, F., Wu, H., Zhou, L., and Wang, Z. (2006) Androgen receptor and prostate apoptosis response factor-4 target the c-FLIP gene to determine survival and apoptosis in the prostate gland, J Mol Endocrinol 36, 463–483.
Cornforth, A. N., Davis, J. S., Khanifar, E., Nastiuk, K. L., and Krolewski, J. J. (2008) FOXO3a mediates the androgen-dependent regulation of FLIP and contributes to TRAIL-induced apoptosis of LNCaP cells, Oncogene 27, 4422–4433.
Huang, H., and Tindall, D. J. (2007) Dynamic FoxO transcription factors, J Cell Sci 120, 2479–2487.
Fu, Z., and Tindall, D. J. (2008) FOXOs, cancer and regulation of apoptosis, Oncogene 27, 2312–2319.
Brunet, A., Bonni, A., Zigmond, M. J., Lin, M. Z., Juo, P., Hu, L. S., Anderson, M. J., Arden, K. C., Blenis, J., and Greenberg, M. E. (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor, Cell 96, 857–868.
Huang, H., and Tindall, D. J. (2006) FOXO factors: a matter of life and death, Future Oncol 2, 83–89.
Huang, H., Muddiman, D. C., and Tindall, D. J. (2004) Androgens negatively regulate forkhead transcription factor FKHR (FOXO1) through a proteolytic mechanism in prostate cancer cells, J Biol Chem 279, 13866–13877.
Lynch, R. L., Konicek, B. W., McNulty, A. M., Hanna, K. R., Lewis, J. E., Neubauer, B. L., and Graff, J. R. (2005) The progression of LNCaP human prostate cancer cells to androgen independence involves decreased FOXO3a expression and reduced p27KIP1 promoter transactivation, Mol Cancer Res 3, 163–169.
Li, P., Lee, H., Guo, S., Unterman, T. G., Jenster, G., and Bai, W. (2003) AKT-independent protection of prostate cancer cells from apoptosis mediated through complex formation between the androgen receptor and FKHR, Mol Cell Biol 23, 104–118.
Wang, D., Montgomery, R. B., Schmidt, L. J., Mostaghel, E. A., Huang, H., Nelson, P. S., and Tindall, D. J. (2009) Reduced tumor necrosis factor receptor-associated death domain expression is associated with prostate cancer progression, Cancer Res 69, 9448–9456.
Hsu, H., Xiong, J., and Goeddel, D. V. (1995) The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation, Cell 81, 495–504.
Jin, Z., and El-Deiry, W. S. (2006) Distinct signaling pathways in TRAIL- versus tumor necrosis factor-induced apoptosis, Mol Cell Biol 26, 8136–8148.
Ermolaeva, M. A., Michallet, M. C., Papadopoulou, N., Utermohlen, O., Kranidioti, K., Kollias, G., Tschopp, J., and Pasparakis, M. (2008) Function of TRADD in tumor necrosis factor receptor 1 signaling and in TRIF-dependent inflammatory responses, Nat Immunol 9, 1037–1046.
Pobezinskaya, Y. L., Kim, Y. S., Choksi, S., Morgan, M. J., Li, T., Liu, C., and Liu, Z. (2008) The function of TRADD in signaling through tumor necrosis factor receptor 1 and TRIF-dependent Toll-like receptors, Nat Immunol 9, 1047–1054.
Huang, S., Pettaway, C. A., Uehara, H., Bucana, C. D., and Fidler, I. J. (2001) Blockade of NF-kappaB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis, Oncogene 20, 4188–4197.
Lessard, L., Karakiewicz, P. I., Bellon-Gagnon, P., Alam-Fahmy, M., Ismail, H. A., Mes-Masson, A. M., and Saad, F. (2006) Nuclear localization of nuclear factor-kappaB p65 in primary prostate tumors is highly predictive of pelvic lymph node metastases, Clin Cancer Res 12, 5741–5745.
Xie, D., Gore, C., Liu, J., Pong, R. C., Mason, R., Hao, G., Long, M., Kabbani, W., Yu, L., Zhang, H., Chen, H., Sun, X., Boothman, D. A., Min, W., and Hsieh, J. T. (2010) Role of DAB2IP in modulating epithelial-to-mesenchymal transition and prostate cancer metastasis, Proc Natl Acad Sci USA 107, 2485–2490.
Frixen, U. H., Behrens, J., Sachs, M., Eberle, G., Voss, B., Warda, A., Lochner, D., and Birchmeier, W. (1991) E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells, J Cell Biol 113, 173–185.
Handschuh, G., Candidus, S., Luber, B., Reich, U., Schott, C., Oswald, S., Becke, H., Hutzler, P., Birchmeier, W., Hofler, H., and Becker, K. F. (1999) Tumour-associated E-cadherin mutations alter cellular morphology, decrease cellular adhesion and increase cellular motility, Oncogene 18, 4301–4312.
Cheng, L., Nagabhushan, M., Pretlow, T. P., Amini, S. B., and Pretlow, T. G. (1996) Expression of E-cadherin in primary and metastatic prostate cancer, Am J Pathol 148, 1375–1380.
Umbas, R., Isaacs, W. B., Bringuier, P. P., Schaafsma, H. E., Karthaus, H. F., Oosterhof, G. O., Debruyne, F. M., and Schalken, J. A. (1994) Decreased E-cadherin expression is associated with poor prognosis in patients with prostate cancer, Cancer Res 54, 3929–3933.
Bussemakers, M. J., Van Bokhoven, A., Tomita, K., Jansen, C. F., and Schalken, J. A. (2000) Complex cadherin expression in human prostate cancer cells, Int J Cancer 85, 446–450.
Gravdal, K., Halvorsen, O. J., Haukaas, S. A., and Akslen, L. A. (2007) A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer, Clin Cancer Res 13, 7003–7011.
Jaggi, M., Nazemi, T., Abrahams, N. A., Baker, J. J., Galich, A., Smith, L. M., and Balaji, K. C. (2006) N-cadherin switching occurs in high Gleason grade prostate cancer, Prostate 66, 193–199.
Liu, Y. N., Liu, Y., Lee, H. J., Hsu, Y. H., and Chen, J. H. (2008) Activated androgen receptor downregulates E-cadherin gene expression and promotes tumor metastasis, Mol Cell Biol 28, 7096–7108.
Jennbacken, K., Tesan, T., Wang, W., Gustavsson, H., Damber, J. E., and Welen, K. (2010) N-cadherin increases after androgen deprivation and is associated with metastasis in prostate cancer, Endocr Relat Cancer 17,469–479.
Patriarca, C., Petrella, D., Campo, B., Colombo, P., Giunta, P., Parente, M., Zucchini, N., Mazzucchelli, R., and Montironi, R. (2003) Elevated E-cadherin and alpha/beta-catenin expression after androgen deprivation therapy in prostate adenocarcinoma, Pathol Res Pract 199, 659–665.
Monks, D. A., and Watson, N. V. (2001) N-cadherin expression in motoneurons is directly regulated by androgens: a genetic mosaic analysis in rats, Brain Res 895, 73–79.
Chu, K., Cheng, C. J., Ye, X., Lee, Y. C., Zurita, A. J., Chen, D. T., Yu-Lee, L. Y., Zhang, S., Yeh, E. T., Hu, M. C., Logothetis, C. J., and Lin, S. H. (2008) Cadherin-11 promotes the metastasis of prostate cancer cells to bone, Mol Cancer Res 6, 1259–1267.
Lee, Y. C., Cheng, C. J., Huang, M., Bilen, M. A., Ye, X., Navone, N. M., Chu, K., Kao, H. H., Yu-Lee, L. Y., Wang, Z., and Lin, S. H. (2010) Androgen depletion up-regulates cadherin-11 expression in prostate cancer, J Pathol 22, 68–76
Zou, Z., Anisowicz, A., Hendrix, M. J., Thor, A., Neveu, M., Sheng, S., Rafidi, K., Seftor, E., and Sager, R. (1994) Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells, Science 263, 526–529.
Zou, Z., Zhang, W., Young, D., Gleave, M. G., Rennie, P., Connell, T., Connelly, R., Moul, J., Srivastava, S., and Sesterhenn, I. (2002) Maspin expression profile in human prostate cancer (CaP) and in vitro induction of Maspin expression by androgen ablation, Clin Cancer Res 8, 1172–1177.
Cher, M. L., Biliran, H. R., Jr., Bhagat, S., Meng, Y., Che, M., Lockett, J., Abrams, J., Fridman, R., Zachareas, M., and Sheng, S. (2003) Maspin expression inhibits osteolysis, tumor growth, and angiogenesis in a model of prostate cancer bone metastasis, Proc Natl Acad Sci USA 100, 7847–7852.
Zhang, M., Volpert, O., Shi, Y. H., and Bouck, N. (2000) Maspin is an angiogenesis inhibitor, Nat Med 6, 196–199.
Sheng, S., Truong, B., Fredrickson, D., Wu, R., Pardee, A. B., and Sager, R. (1998) Tissue-type plasminogen activator is a target of the tumor suppressor gene maspin, Proc Natl Acad Sci USA 95, 499–504.
Yin, S., Lockett, J., Meng, Y., Biliran, H., Jr., Blouse, G. E., Li, X., Reddy, N., Zhao, Z., Lin, X., Anagli, J., Cher, M. L., and Sheng, S. (2006) Maspin retards cell detachment via a novel interaction with the urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor system, Cancer Res 66, 4173–4181.
He, M. L., Jiang, A. L., Zhang, P. J., Hu, X. Y., Liu, Z. F., Yuan, H. Q., and Zhang, J. Y. (2005) Identification of androgen-responsive element ARE and Sp1 element in the maspin promoter, Chin J Physiol 48, 160–166.
Tran, C., Ouk, S., Clegg, N. J., Chen, Y., Watson, P. A., Arora, V., Wongvipat, J., Smith-Jones, P. M., Yoo, D., Kwon, A., Wasielewska, T., Welsbie, D., Chen, C. D., Higano, C. S., Beer, T. M., Hung, D. T., Scher, H. I., Jung, M. E., and Sawyers, C. L. (2009) Development of a second-generation antiandrogen for treatment of advanced prostate cancer, Science 324, 787–790.
Scher, H. I., Beer, T. M., Higano, C. S., Anand, A., Taplin, M. E., Efstathiou, E., Rathkopf, D., Shelkey, J., Yu, E. Y., Alumkal, J., Hung, D., Hirmand, M., Seely, L., Morris, M. J., Danila, D. C., Humm, J., Larson, S., Fleisher, M., and Sawyers, C. L. (2010) Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study, Lancet 375, 1437–1446.
Andriole, G. L., Bostwick, D. G., Brawley, O. W., Gomella, L. G., Marberger, M., Montorsi, F., Pettaway, C. A., Tammela, T. L., Teloken, C., Tindall, D. J., Somerville, M. C., Wilson, T. H., Fowler, I. L., and Rittmaster, R. S. (2010) Effect of dutasteride on the risk of prostate cancer, N Engl J Med 362, 1192–1202.
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Wang, D., Tindall, D.J. (2011). Androgen Action During Prostate Carcinogenesis. In: Saatcioglu, F. (eds) Androgen Action. Methods in Molecular Biology, vol 776. Humana Press. https://doi.org/10.1007/978-1-61779-243-4_2
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DOI: https://doi.org/10.1007/978-1-61779-243-4_2
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