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,Chawnshang Chang

doi:10.1074/jbc.m204751200

Abstract

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.

Highlights

The ubiquitin-proteasome system degrades misfolded or unfolded proteins in order to control a variety of biological functions, including cell proliferation, differentiation, and stress response [1,2,3]
The Proteasome Activity Is Required for androgen receptor (AR) Transactivation—Androgen/AR signaling plays important roles in prostate cancer cell growth and cell apoptosis (29 –32)
In accordance with previous reports [16, 17], we observed that MG132 (5 ␮M) could markedly induce apoptosis in prostate cancer LNCaP cells (Fig. 1)

Summary

The abbreviations used are

E2, ubiquitin-conjugating enzyme; E3, ubiquitin-protein ligase; AR, androgen receptor; DHT, 5␣-dihydrotestosterone; MMTV-luc, mouse mammary tumor virus-luciferase; PSA, prostate specific antigen; GR, glucocorticoid receptor; Dex, dexamethasone; ARE, androgen response element; DAPI, 4,6-diamidino-2-phenylindole; TUNEL, terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling.

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION