This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chun, J. Y. Articles by Gao, A. C. Search for Related Content PubMed PubMed Citation Articles by Chun, J. Y. Articles by Gao, A. C.

Research Articles: Therapeutics

Mechanisms of selenium down-regulation of androgen receptor signaling in prostate cancer

Departments of Medicine and Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York

Requests for reprints: Allen C. Gao, Grace Cancer Drug Center, Departments of Medicine and Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-1201; Fax: 716-845-8857. E-mail: allen.gao{at}roswellpark.org

Abstract

Prevention trials showed that selenium reduced prostate cancer incidence by 50%, establishing selenium as a promising chemopreventive agent for prostate cancer. Selenium inhibited human prostate cancer cell growth, blocked cell cycle progression at multiple transition points, and induced apoptotic cell death. Previous studies showed a novel mechanism of selenium anticancer action in which selenium markedly reduces androgen signaling and androgen receptor (AR)–mediated gene expression, including prostate-specific antigen (PSA), in human prostate cancer cells. The molecular mechanisms of selenium-mediated down-regulation of AR signaling are not clear. In this study, a systemic approach was taken to examine the modification of androgen signaling by selenium in human prostate cancer cells. In addition to reduced AR mRNA expression, selenium was found to initially increase the stability of AR mRNA within 6 hours while decreasing the stability of AR mRNA after 8 hours. Selenium increased AR protein degradation and reduced AR nuclear localization. Scatchard analysis indicated that selenium did not affect ligand binding to AR in LNCaP cells. Chromatin immunoprecipitation analyses showed that DHT increased the recruitment of AR and coactivators, such as SRC-1 and TIF-2, to the promoter of the PSA gene, and that recruitment was greatly diminished in the presence of 5 µmol/L selenium. On the other hand, selenium enhanced the recruitment of corepressors, such as SMRT, to the promoter of the PSA gene. Taken together, these results suggest that selenium disrupts AR signaling at multiple stages, including AR mRNA expression, mRNA stability, protein degradation, nuclear translocation, and recruitment of coregulators. [Mol Cancer Ther 2006;5(4):913–8]

Grant support: NIH grants CA90271 and CA109441, U.S. Army Medical Research Materiel Command AMRMC Prostate Cancer Research Program grant DAMD17-01-1-0089, and Roswell Park Alliance Foundation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: J.Y. Chun and N. Nadiminty contributed equally to this work.

Received 9/26/05; revised 1/11/06; accepted 1/25/06.

This article has been cited by other articles:

				J. Y. Chun, Y. Hu, E. Pinder, J. Wu, F. Li, and A. C. Gao Selenium inhibition of survivin expression by preventing Sp1 binding to its promoter Mol. Cancer Ther., September 1, 2007; 6(9): 2572 - 2580. [Abstract] [Full Text] [PDF]

				J. Guo, C. Jiang, Z. Wang, H.-J. Lee, H. Hu, B. Malewicz, H.-J. Lee, J.-H. Lee, N.-I. Baek, J.-H. Jeong, et al. A novel class of pyranocoumarin anti-androgen receptor signaling compounds Mol. Cancer Ther., March 1, 2007; 6(3): 907 - 917. [Abstract] [Full Text] [PDF]