Peroxisome proliferator-activated receptor gamma coactivator-1alpha interacts with the androgen receptor (AR) and promotes prostate cancer cell growth by activating the AR.
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 gamma coactivator-1alpha (PGC-1alpha) was found to be an AR cofactor. PGC-1alpha 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-1alpha suppressed cell growth of AR-expressing prostate cancer (PCa) cells by inducing cell-cycle arrest at the G(1) phase, similar to inhibition of androgen/AR signaling. Furthermore, PGC-1alpha knock-down also suppressed cell growth in the castration-resistant LNCaP-derivatives. These findings indicate that PGC-1alpha is involved in the proliferation of AR-expressing PCa cells by acting as an AR coactivator. Modulation of PGC-1alpha 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.
Shiota
Masaki
M
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
Yokomizo
Akira
A
Tada
Yasuhiro
Y
Inokuchi
Junichi
J
Tatsugami
Katsunori
K
Kuroiwa
Kentaro
K
Uchiumi
Takeshi
T
Fujimoto
Naohiro
N
Seki
Narihito
N
Naito
Seiji
S
D000728:Androgens / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins; D004742:Enhancer Elements, Genetic; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D055767:Immobilized Proteins; D008297:Male; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D054730:Protein Interaction Domains and Motifs; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015533:Transcriptional Activation
D000728:Androgens; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D055767:Immobilized Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D014157:Transcription Factors; D017430:Prostate-Specific Antigen