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

Departments of Urology (M.S., A.Y., Y.T., J.I., K.T., K.K., N.S., S.N.) and Clinical Chemistry and Laboratory Medicine (T.U.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8252, Japan; and Department of Urology (N.F.), School of Medicine, University of Occupational and Environmental Health 807-8555, Kitakyushu, Japan

Address all correspondence and requests for reprints to: Akira Yokomizo M.D., Ph.D., Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8252, Japan. E-mail: yokoa{at}uro.med.kyushu-u.ac.jp.

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.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

Coregulators:   PGC-1

Ligands:   Dihydrotestosterone

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