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Nuclear receptors are a superfamily of ligand-activated transcription factors that play critical roles in the regulation of normal biological processes and several disease states. Of the nuclear receptors expressed within the prostate, the androgen receptor (AR) promotes the differentiation of prostatic epithelial cells and stimulates production of enzymes needed for liquefaction of semen. Multiple forms of AR also promote the growth of both early and late stage prostate cancers. As a result, drugs that target the AR signaling pathway are routinely used to treat patients with advanced forms of prostate cancer. Data also suggest that a second member of the nuclear receptor superfamily, the peroxisome proliferator activated receptor gamma (PPARγ), is a tumor suppressor that regulates growth of normal prostate and prostate cancers. Recent studies indicate there is a bidirectional interaction between AR and PPARγ, with each receptor influencing the expression and/or activity of the other within prostatic tissues. In this review, we examine how AR and PPARγeach regulate the growth and development of normal prostatic epithelial cells and prostate cancers. We also discuss interactions between the AR and PPARγsignaling pathways and how those interactions may influence prostate biology.

The peroxisome proliferator activated receptor gamma (PPARγ) is a ligand‐activated transcription factor that regulates growth and differentiation within normal prostate and prostate cancers. However the factors that control PPARγ within the prostate cancers have not been characterized. The goal of this study was to examine whether the androgen receptor (AR) regulates PPARγ expression and function within human prostate cancer cells. qRT‐PCR and Western blot analyses revealed nanomolar concentrations of the AR agonist dihydrotestosterone (DHT) decrease PPARγ mRNA and protein within the castration‐resistant, AR‐positive C4‐2 and VCaP human prostate cancer cell lines. The AR antagonists bicalutamide and enzalutamide blocked the ability of DHT to reduce PPARγ levels. In addition, siRNA mediated knockdown of AR increased PPARγ protein levels and ligand‐induced PPARγ transcriptional activity within the C4‐2 cell line. Furthermore, proteasome inhibitors that interfere with AR function increased the level of basal PPARγ and prevented the DHT‐mediated suppression of PPARγ. These data suggest that AR normally functions to suppress PPARγ expression within AR‐positive prostate cancer cells. To determine whether increases in AR protein would influence PPARγ expression and activity, we used lipofectamine‐based transfections to overexpress AR within the AR‐null PC‐3 cells. The addition of AR to PC‐3 cells did not significantly alter PPARγ protein levels. However, the ability of the PPARγ ligand rosiglitazone to induce activation of a PPARγ‐driven luciferase reporter and induce expression of FABP4 was suppressed in AR‐positive PC‐3 cells. Together, these data indicate AR serves as a key modulator of PPARγ expression and function within prostate tumors. J. Cell. Physiol. 231: 2664–2672, 2016. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

The peroxisome proliferator activated receptor gamma (PPARγ) is a ligand-activated transcription factor that regulates in vitro and in vivo growth of castration-resistant human prostate cancer (PCa) cells. However, the factors that control expression of PPARγ within human PCa have not been characterized. We have previously shown that the androgen dihydrotestosterone decreases PPARγ levels and transcriptional activity in human PCa cells. Dihydrotestosterone serves as a high affinity ligand for the 110 kD form of the androgen receptor (AR-FL). Recent studies have shown the development of castration-resistant forms of prostate cancer is not only due to reactivation of AR-FL but also results from the expression of androgen receptor splice variants (ARVs) that lack the ligand-binding domain of the receptor. The goal of this study is to define the extent to which AR-FL and an ARV found in castration-resistant prostate cancer, AR-V7, regulate PPARγ expression and function. We first examined the role of AR-FL in the AR-positive C4-2 cell line. siRNA-mediated knockdown of endogenous AR-FL within C4-2 cells increased PPARγ protein and transcriptional activity. We next used reporter assays to further define the role of AR-FL and AR-V7 in PPARγ function. In these experiments, we first transfected plasmid vectors that express the AR-V7 or AR-FL into the AR null PC-3 prostate cancer cell line. A luciferase-based reporter assay was then used to measure alterations in PPARγ transcriptional activity within transfected cells. The addition of AR-FL to PC-3 cells resulted in reduced basal PPARγ luciferase activity. The ability of the ligand rosiglitazone to increase PPARγ activation was also suppressed in AR-FL positive PC-3 cells. A comparable decrease in ligand-induced PPARγ activation was detected in PC-3 cells that expressed AR-V7. The reduction in PPARγ activity produced by AR-FL and AR-V7 was likely not due to alterations in PPAR gamma expression, for we did not detect a consistent reduction in PPARγ mRNA and protein in transfected cells. Overall these data suggest that both AR-FL and AR-V7 are negative regulators of PPARγ function. Moreover, the AR-V7 stimulated reduction in PPARγ activity does not require the presence of AR-FL. Studies currently are underway to define the effect of endogenous AR-V7 on PPARγ expression and activity. This project was supported by NIGMS RISE grant (2R25GM059994-13), a NCI Mentored Career Development Award (K01CA114253), and the Vanderbilt CTSA grant UL1 RR024975-01 from NCRR/NIH. Citation Format: Emuejevoke Olokpa, Lamonica V. Stewart. PPARγ function is attenuated by full length androgen receptor and the AR-V7 variant in human prostate cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1848. doi:10.1158/1538-7445.AM2015-1848