The androgen receptor in hormone-refractory prostate cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Mao HL
PROVIDER: S-EPMC3735219 | biostudies-other | 2009 Jan
REPOSITORIES: biostudies-other
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Project description:Integration of cellular signaling pathways with androgen receptor (AR) signaling can be achieved through phosphorylation of AR by cellular kinases. However, the kinases responsible for phosphorylating the AR at numerous sites and the functional consequences of AR phosphorylation are only partially understood. Bioinformatic analysis revealed AR serine 213 (S213) as a putative substrate for PIM1, a kinase overexpressed in prostate cancer. Therefore, phosphorylation of AR serine 213 by PIM1 was examined using a phosphorylation site-specific antibody. Wild-type PIM1, but not catalytically inactive PIM1, specifically phosphorylated AR but not an AR serine-to-alanine mutant (S213A). In vitro kinase assays confirmed that PIM1 can phosphorylate AR S213 in a ligand-independent manner and cell type-specific phosphorylation was observed in prostate cancer cell lines. Upon PIM1 overexpression, AR phosphorylation was observed in the absence of hormone and was further increased in the presence of hormone in LNCaP, LNCaP-abl and VCaP cells. Moreover, phosphorylation of AR was reduced in the presence of PIM kinase inhibitors. An examination of AR-mediated transcription showed that reporter gene activity was reduced in the presence of PIM1 and wild-type AR, but not S213A mutant AR. Androgen-mediated transcription of endogenous PSA, Nkx3.1 and IGFBP5 was also decreased in the presence of PIM1, whereas IL6, cyclin A1 and caveolin 2 were increased. Immunohistochemical analysis of prostate cancer tissue microarrays showed significant P-AR S213 expression that was associated with hormone refractory prostate cancers, likely identifying cells with catalytically active PIM1. In addition, prostate cancers expressing a high level of P-AR S213 were twice as likely to be from biochemically recurrent cancers. Thus, AR phosphorylation by PIM1 at S213 impacts gene transcription and is highly prevalent in aggressive prostate cancer.
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Project description:This study examined androgen receptor (AR) gene amplification and protein expression in 102 matched paired hormone sensitive and resistant tumours from 51 patients. AR gene amplification and X chromosome copy number were assessed by fluorescent in situ hybridisation, and protein expression was assessed by immunohistochemistry. All tumours were stained for PSA protein expression. Significantly more tumours exhibited AR amplification following the development of hormone resistance (20%, 10 out of 49) compared to matched hormone-sensitive tumours from the same patient (2%, one out of 48) (P=0.0085). The level of AR expression was significantly higher in hormone-resistant tumours compared to matched hormone-sensitive tumours from the same patient (130, interquartile range, 55-167 vs 94.5 interquartile range, 55-120, P=0.019). AR expression levels in hormone-resistant tumours with and without AR amplification were not significantly different. However, an increase in AR expression was seen with the development of AR amplification in paired tumours. The rate of AR gene amplification and/or an increase in AR protein expression during androgen resistant is too low to wholly explain the development of androgen resistance. Alternative mechanisms for modulating the function of the AR, or other signalling pathways, must be considered as key factors in the development of hormone-resistant prostate.
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Project description:The standard hormonal therapy with currently available antiandrogens and the leutinizing hormone releasing hormone (LHRH) analogs is not effective in the hormone-refractory stage of prostate cancer due to changes in androgen receptor (AR) signaling axis. In this refractory stage, AR continues to play a significant role in the growth of cancer cells even though the cancer cells are no longer dependent on the level of circulating androgens.A series of 11beta-Delta(9)-19 nortestosterone compounds were designed through structure-based rationale and tested for their binding affinity against AR and glucocorticoid receptor (GR) using fluorescence polarization assays, their agonistic ability to induce AR dependent transcription using PSA-driven report gene assays, and their growth inhibitory affects against a series of AR positive (LAPC4, LNCap, and CWR22R) and negative human prostate cancer cell lines (PC3) using MTT cell proliferation assays.This study proposes the design of novel bifunctional antiandrogens based on the conjugation of 11beta and/or 7alpha-Delta(9)-19 nortestosterone class of steroidal compounds to the synthetic ligand for FK506-binding proteins. As a critical step towards the development of bifunctional antiandrogens, highly potent and AR-specific lead compounds were identified using in vitro data. The lead compounds identified in this study possessed low binding affinity for GR, indicating the absence of undesirable antiglucocorticoid activity.The results of this study validate our drug discovery rationale based on the structural biology of AR and pave the pay for future development of bifunctional compounds in order to block AR function in hormone refractory stage of prostate cancer.
| S-EPMC3087493 | biostudies-literature
Project description:Suppression of androgen production and function provides palliation but not cure in men with prostate cancer (PCa). Therapeutic failure and progression to hormone-refractory PCa (HRPC) are often accompanied by molecular alterations involving the androgen receptor (AR). In this study, we report novel forms of AR alteration that are prevalent in HRPC. Through in silico sequence analysis and subsequent experimental validation studies, we uncovered seven AR variant transcripts lacking the reading frames for the ligand-binding domain due to splicing of "intronic" cryptic exons to the upstream exons encoding the AR DNA-binding domain. We focused on the two most abundantly expressed variants, AR-V1 and AR-V7, for more detailed analysis. AR-V1 and AR-V7 mRNA showed an average 20-fold higher expression in HRPC (n = 25) when compared with hormone-naive PCa (n = 82; P < 0.0001). Among the hormone-naive PCa, higher expression of AR-V7 predicted biochemical recurrence following surgical treatment (P = 0.012). Polyclonal antibodies specific to AR-V7 detected the AR-V7 protein frequently in HRPC specimens but rarely in hormone-naive PCa specimens. AR-V7 was localized in the nuclei of cultured PCa cells under androgen-depleted conditions, and constitutively active in driving the expression of canonical androgen-responsive genes, as revealed by both AR reporter assays and expression microarray analysis. These results suggest a novel mechanism for the development of HRPC that warrants further investigation. In addition, as expression markers for lethal PCa, these novel AR variants may be explored as potential biomarkers and therapeutic targets for advanced PCa.
| S-EPMC2614301 | biostudies-literature
Project description:Prostate cancer (PCa) growth is mainly driven by androgen receptor (AR), and tumors that initially respond to androgen deprivation therapy (ADT) or AR inhibition usually relapse into a more aggressive, castration-resistant PCa (CRPC) stage. Circulating growth hormone (GH) has a permissive role in PCa development in animal models and in human PCa xenograft growth. As GH and GH receptor (GHR) are both expressed in PCa cells, we assessed whether prostatic GH production is linked to AR activity and whether GH contributes to the castration-resistant phenotype. Using online datasets, we found that GH is highly expressed in human CRPC. We observed increased GH expression in castration-resistant C4-2 compared with castration-sensitive LNCaP cells as well as in enzalutamide (MDV3100)-resistant (MDVR) C4-2B (C4-2B MDVR) cells compared with parental C4-2B. We describe a negative regulation of locally produced GH by androgens/AR in PCa cells following treatment with AR agonists (R1881) and antagonists (enzalutamide, bicalutamide). We also show that GH enhances invasive behavior of CRPC 22Rv1 cells, as reflected by increased migration, invasion, and anchorage-independent growth, as well as expression of matrix metalloproteases. Moreover, GH induces expression of the AR splice variant 7, which correlates with antiandrogen resistance, and also induces insulinlike growth factor 1, which is implicated in PCa progression and ligand-independent AR activation. In contrast, blockade of GH action with the GHR antagonist pegvisomant reverses these effects both in vitro and in vivo. GH induction following ADT or AR inhibition may contribute to CRPC progression by bypassing androgen growth requirements.
| S-EPMC5505214 | biostudies-literature
Project description:Canine prostate cancer (PC) is an aggressive disease, and dogs can be considered comparative models for human PC. In recent years, canine PC has been shown to resemble human castrate-resistant prostate cancer. The influx and efflux of testosterone in prostatic luminal cells are regulated by P-glycoprotein (P-gp). Therefore, human PC generally lacks P-gp expression and maintains the expression of androgen receptors (ARs). However, this co-expression has not previously been investigated in dogs. Therefore, this study aimed to evaluate AR and P-gp co-expression to elucidate these protein patterns in canine prostate samples. We identified AR/P-gp double immunofluorescence co-expression of both proteins in normal luminal cells. However, in canine PC, cells lack AR expression and exhibit increased P-gp expression. These results were confirmed by gene expression analyses. Overall, our results strongly suggest that normal canine prostate testosterone influx may be regulated by P-gp expression, and that during progression to PC, prostatic cells lack AR expression and P-gp overexpress. P-gp expression in canine PC may be related to a phenotype of multiple drug resistance.
| S-EPMC8835304 | biostudies-literature
Project description:BackgroundAndrogen receptor (AR)-gene amplification, found in 20-30% of castration-resistant prostate cancer (CRPCa) is proposed to develop as a consequence of hormone-deprivation therapy and be a prime cause of treatment failure. Here we investigate AR-gene amplification in cancers before hormone deprivation therapy.MethodsA tissue microarray (TMA) series of 596 hormone-naive prostate cancers (HNPCas) was screened for chromosome X and AR-gene locus-specific copy number alterations using four-colour fluorescence in situ hybridisation.ResultsBoth high level gain in chromosome X (≥4 fold; n=4, 0.7%) and locus-specific amplification of the AR-gene (n=6, 1%) were detected at low frequencies in HNPCa TMAs. Fluorescence in situ hybridisation mapping whole sections taken from the original HNPCa specimen blocks demonstrated that AR-gene amplifications exist in small foci of cells (≤ 600 nm, ≤1% of tumour volume). Patients with AR gene-locus-specific copy number gains had poorer prostate cancer-specific survival.ConclusionSmall clonal foci of cancer containing high level gain of the androgen receptor (AR)-gene develop before hormone deprivation therapy. Their small size makes detection by TMA inefficient and suggests a higher prevalence than that reported herein. It is hypothesised that a large proportion of AR-amplified CRPCa could pre-date hormone deprivation therapy and that these patients would potentially benefit from early total androgen ablation.
| S-EPMC3960602 | biostudies-literature
Project description:Androgen receptor (AR)-mediated oncogenic pathways have not been fully elucidated. In this study, we used high-throughput microarray analysis on two AR-positive prostate cancer (CaP) cell lines to identify 16 AR-responsive microRNAs (miRNA). We focused on miR-21 because of its previously reported oncogenic activity in other cancers. We show androgen-induced AR binding to the defined miR-21 promoter, miPPR-21, suggesting direct transcriptional regulation. Inhibition of miR-21 diminished androgen-induced CaP cell proliferation, providing new evidence that miRNAs can contribute to androgen-driven cell growth. Elevated expression of miR-21 enhanced CaP tumor growth in vivo and, surprisingly, was sufficient for androgen-dependent tumors to overcome castration-mediated growth arrest. Thus, elevated miR-21 expression alone is sufficient to impart castration resistance. Moreover, quantitative reverse transcription-PCR analysis revealed elevated miR-21 expression in CaP when compared with adjacent normal tissue. These results suggest that miR-21 may contribute to CaP pathogenesis.
| S-EPMC2861586 | biostudies-literature
Project description:Androgen deprivation (AD) is an effective method for initially suppressing prostate cancer (PC) progression. However, androgen-refractory PC cells inevitably emerge from the androgen-responsive tumor, leading to incurable disease. Recent studies have shown AD induces cellular senescence, a phenomenon that is cell-autonomously tumor-suppressive but which confers tumor-promoting adaptations that can facilitate the advent of senescence-resistant malignant cell populations. Because androgen-refractory PC cells emerge clonally from the originally androgen-responsive tumor, we sought to investigate whether AD-induced senescence (ADIS) affects acquisition of androgen-refractory behavior in androgen-responsive LNCaP and LAPC4 prostate cancer cells. We find that repeated exposure of these androgen-responsive cells to senescence-inducing stimuli via cyclic AD leads to the rapid emergence of ADIS-resistant, androgen-refractory cells from the bulk senescent cell population. Our results show that the ADIS phenotype is associated with tumor-promoting traits, notably chemoresistance and enhanced pro-survival mechanisms such as inhibition of p53-mediated cell death, which encourage persistence of the senescent cells. We further find that pharmacologic enforcement of p53/Bax activation via Nutlin-3 prior to establishment of ADIS is required to overcome the associated pro-survival response and preferentially trigger pervasive cell death instead of senescence during AD. Thus our study demonstrates that ADIS promotes outgrowth of androgen-refractory PC cells and is consequently a suboptimal tumor-suppressor response to AD.
| S-EPMC3695935 | biostudies-literature
Project description:Second-generation androgen receptor axis-targeted (ARAT) agents, namely abiraterone and enzalutamide, enable stronger blockade of the androgen receptor (AR) axis and longer survival of men with castration-resistant prostate cancer (CRPC). However, the extent of the improved survival remains insufficient and the majority of patients eventually develop resistance to these novel agents. Some patients develop resistance against ARAT treatment through mechanisms termed "complete AR independence" or "AR indifference", and no longer require activation of the AR axis. However, a considerable proportion of CRPC patients remain persistently dependent on AR or its downstream signaling pathways. Ligand-independent activation of the AR, an AR axis-dependent mechanism, is mediated by truncated forms of ARs that lack the ligand-binding domain (LBD), arising as products of AR splicing variants or nonsense mutations of AR. Post-translational modifications of ARs can also contribute to ligand-independent transactivation of the AR. Other mechanisms for AR axis activation are mediated by pathways that bypass the AR. Recent studies revealed that the glucocorticoid receptor can upregulate a similar transcription program to that of the AR, thus bypassing the AR. ARAT agents are essentially ineffective for CRPC driven by these AR-independent mechanisms. This review article describes recent efforts to overcome these refractory machineries for the development of next-generation AR axis blockade in CRPC.
| S-EPMC6210307 | biostudies-literature