Peroxisome Proliferator-Activated Receptor {gamma} Coactivator-1{alpha} Interacts with the Androgen Receptor (AR) and Promotes Prostate Cancer Cell Growth by Activating the AR

M Shiota, A Yokomizo, Y Tada, J Inokuchi, K Tatsugami, K Kuroiwa, T Uchiumi, N Fujimoto, N Seki and S. Naito

Molecular Endocrinology, 2010, 24(1), 114-127. DOI: 10.1210/me.2009-0302

Abstract

There are currently few successful therapies for castration-resistant prostate cancer (CRPC). CRPC is thought to result from augmented activation of the androgen/androgen receptor (AR) signaling pathway, which could be enhanced by AR cofactors. In this study, peroxisome proliferator-activated receptor coactivator-1 (PGC-1) was found to be an AR cofactor. PGC-1 interacted with the N-terminal domain of AR, was involved in the N- and C-terminal interaction of AR, and enhanced the DNA-binding ability of AR to androgen-responsive elements in the prostate-specific antigen enhancer and promoter regions to increase the transcription of AR target genes. Silencing of PGC-1 suppressed cell growth of AR-expressing prostate cancer (PCa) cells by inducing cell-cycle arrest at the G1 phase, similar to inhibition of androgen/AR signaling. Furthermore, PGC-1 knock-down also suppressed cell growth in the castration-resistant LNCaP-derivatives. These findings indicate that PGC-1 is involved in the proliferation of AR-expressing PCa cells by acting as an AR coactivator. Modulation of PGC-1 expression or function may offer a useful strategy for developing novel therapeutics for PCa, including CRPC, which depends on AR signaling by overexpressing AR and its coactivators.

ASCI-ID: 1324-172