Abstract
Abstract Androgens suppress TGF-beta responses in the prostate through mechanisms that are not fully explored. We have recently reported that 5a-dihydrotestosterone (DHT) suppresses the ability of TGF-beta to inhibit proliferation and to induce apoptosis of prostatic epithelial cells, and provided evidence that such suppression was fueled by the transcriptional downregulation of TGF-beta receptor II (TbRII). We now show that AR activated by DHT suppresses the TGF-beta-induced phosphorylation of Smad3 in LNCaP cells overexpressing TbRII under the control of a CMV promoter, suggesting that transcriptional repression of TbRII alone does not fully account for the impact of DHT on TGF-beta responses. Instead, we demonstrate that such suppression occurs through loss of total Smad3, resulting from transcriptional suppression of Smad3. Consistent with this mechanism, we report that loss of Smad3 mRNA inversely correlates with elevated AR mRNA in a cohort of human prostate tissues (p < 0.0001). We provide evidence that DHT downregulates the promoter activity of Smad3 in various prostate cancer cell lines, including NRP-154+AR, DU145+AR, LNCaP, and VCaP, at least partly through androgen-dependent inactivation of Sp1. Moreover, we show that overexpression of Smad3 reverses the ability of DHT to protect against TGF-beta-induced apoptosis in NRP-154, supporting our model that loss of Smad3 by DHT is involved in the protection against TGF-beta-induced apoptosis. Together, these findings suggest that deregulated/enhanced expression and activation of AR in prostate carcinomas may intercept the tumor suppressor function of TGF-beta through transcriptional suppression of Smad3, thereby providing new mechanistic insight on the development of castration-resistant prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3967.
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