DHT Selectively Reverses Smad3-Mediated/TGF-β-Induced Responses through Transcriptional Down-Regulation of Smad3 in Prostate Epithelial Cells

Author:

Song Kyung1,Wang Hui12,Krebs Tracy L.1,Wang Bingcheng23,Kelley Thomas J.24,Danielpour David125

Affiliation:

1. Case Comprehensive Cancer Center Research Laboratories (K.S., H.W., T.L.K., D.D.), Cleveland, Ohio 44106

2. The Division of General Medical Sciences-Oncology, Department of Pharmacology (H.W., B.W., T.J.K., D.D.), Cleveland, Ohio 44106

3. Rammelkamp Center for Research (B.W.), Department of Medicine, MetroHealth Campus, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44109

4. Department of Pediatrics (T.J.K.), Division of Pediatric Hematology/Oncology, Rainbow Babies and Children’s Hospital, Case Western Reserve University, Cleveland, Ohio 44106

5. Department of Urology (D.D.), Cleveland, Ohio 44106

Abstract

AbstractAndrogens suppress TGF-β responses in the prostate through mechanisms that are not fully explored. We have recently reported that 5α-dihydrotestosterone (DHT) suppresses the ability of TGF-β to inhibit proliferation and induce apoptosis of prostatic epithelial cells and provided evidence that such suppression was fueled by transcriptional down-regulation of TGF-β receptor II (ΤβRII). We now show that androgen receptor (AR) activated by DHT suppresses the TGF-β-induced phosphorylation of Sma- and Mad-related protein (Smad)3 in LNCaP cells overexpressing TβRII under the control of a cytomegalovirus promoter, which is not regulated by DHT, suggesting that transcriptional repression of TβRII alone does not fully account for the impact of DHT on TGF-β responses. Instead, we demonstrate that such suppression occurs through loss of total Smad3, resulting from transcriptional suppression of Smad3. We provide evidence that DHT down-regulates 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-β-induced apoptosis in NRP-154+AR, supporting our model that loss of Smad3 by DHT is involved in the protection against TGF-β-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-β through transcriptional suppression of Smad3, thereby providing new mechanistic insight into the development of castration-resistant prostate cancer.

Publisher

The Endocrine Society

Subject

Endocrinology,Molecular Biology,General Medicine

Reference52 articles.

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4. Negative regulation of TGF-β receptor/Smad signal transduction.;Itoh;Curr Opin Cell Biol,2007

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