Peroxisome proliferator-activated receptor gamma coactivator-1alpha interacts with the androgen receptor (AR) and promotes prostate cancer cell growth by activating the AR.
Peroxisome proliferator-activated receptor gamma coactivator-1alpha interacts with the androgen receptor (AR) and promotes prostate cancer cell growth by activating the AR.
复制标题
DOI：
10.1210/me.2009-0302
复制
发表时间：
2010
影响因子：
--
通讯作者：
M. Shiota;A. Yokomizo;Y. Tada;J. Inokuchi;K. Tatsugami;K. Kuroiwa;T. Uchiumi;N. Fujimoto;N. Seki;S. Naito
中科院分区：
文献类型：
--
作者：
M. Shiota;A. Yokomizo;Y. Tada;J. Inokuchi;K. Tatsugami;K. Kuroiwa;T. Uchiumi;N. Fujimoto;N. Seki;S. Naito
目前，去势抵抗性前列腺癌（CRPC）的成功疗法很少。CRPC被认为是由雄激素/雄激素受体（AR）信号通路的增强激活引起的，AR辅因子可以增强该信号通路。在这项研究中，过氧化物酶体增殖物激活受体γ辅激活因子-1 α（PGC-1 α）被发现是一种AR辅因子。PGC-1 α与AR的N-末端结构域相互作用，参与AR的N-和C-末端相互作用，并增强AR与前列腺特异性抗原增强子和启动子区域中的雄激素应答元件的DNA结合能力，以增加AR靶基因的转录。沉默PGC-1 α通过诱导细胞周期停滞在G（1）期来抑制AR表达前列腺癌（PCa）细胞的细胞生长，类似于抑制雄激素/AR信号传导。此外，PGC-1 α敲低也抑制去势抗性LNCaP衍生物中的细胞生长。这些发现表明PGC-1 α通过作为AR共激活剂参与AR表达PCa细胞的增殖。PGC-1 α表达或功能的调节可能为开发PCa（包括CRPC）的新疗法提供有用的策略，CRPC依赖于通过过表达AR及其共激活因子的AR信号传导。
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.