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J. Biol. Chem. 277 (39): 36570-36576

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Proteasome Activity Is Required for Androgen Receptor Transcriptional Activity via Regulation of Androgen Receptor Nuclear Translocation and Interaction with Coregulators in Prostate Cancer Cells*

Hui-Kuan Lin, Saleh Altuwaijri, Wen-Jye Lin, Pu-Yeh Kan, Loretta L. Collins, and Chawnshang ChangDagger

From the George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Cancer Center, University of Rochester Medical Center, Rochester, New York 14642

Upon binding to androgen, the androgen receptor (AR) can translocate into the nucleus and bind to androgen response element(s) to modulate its target genes. Here we have shown that MG132, a 26 S proteasome inhibitor, suppressed AR transactivation in an androgen-dependent manner in prostate cancer LNCaP and PC-3 cells. In contrast, MG132 showed no suppressive effect on glucocorticoid receptor transactivation. Additionally, transfection of PSMA7, a proteasome subunit, enhanced AR transactivation in a dose-dependent manner. The suppression of AR transactivation by MG132 may then result in the suppression of prostate-specific antigen, a well known marker used to monitor the progress of prostate cancer. Further mechanistic studies indicated that MG132 may suppress AR transactivation via inhibition of AR nuclear translocation and/or inhibition of interactions between AR and its coregulators, such as ARA70 or TIF2. Together, our data suggest that the proteasome system plays important roles in the regulation of AR activity in prostate cancer cells and may provide a unique target site for the development of therapeutic drugs to block androgen/AR-mediated prostate tumor growth.


* This work was supported by National Institutes of Health Grants DK60948 and DK60905.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed. Tel.: 585-273-4501; Fax: 585-756-4133; E-mail: chang@urmc.rochester.edu; website: www. urmc.rochester.edu/ChangARlab.


Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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