Hsu Cheng-Lung, Chen Yuh-Ling, Ting Huei-Ju, Lin Wen-Jye, Yang Zhiming, Zhang Yanqing, Wang Liang, Wu Chun-Te, Chang Hong-Chiang, Yeh Shuyuan, Pimplikar Sanjay W, Chang Chawnshang
The George H. Whipple Laboratory for Cancer Research, Department of Pathology, and the Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USA.
Mol Endocrinol. 2005 Feb;19(2):350-61. doi: 10.1210/me.2004-0190. Epub 2004 Oct 28.
Early reports showed that androgen receptor (AR) NH2- and COOH-terminal (N-C) interaction was important for full AR function. However, the influence of these interactions on the AR in vivo effects remains unclear. Here we tested some AR-associated peptides and coregulators to determine their influences on AR N-C interaction, AR transactivation, and AR coregulator function. The results showed that AR coactivators such as ARA70N, gelsolin, ARA54, and SRC-1 can enhance AR transactivation but showed differential influences on the N-C interaction. In contrast, AR corepressors ARA67 and Rad9 can suppress AR transactivation, with ARA67 enhancing and Rad9 suppressing AR N-C interaction. Furthermore, liganded AR C terminus-associated peptides can block AR N-C interaction, but only selective peptides can block AR transactivation and coregulator function. We found all the tested peptides can suppress prostate cancer LNCaP cell growth at different levels in the presence of 5alpha-dihydrotestosterone, but only the tested FXXLF-containing peptides, not FXXMF-containing peptides, can suppress prostate cancer CWR22R cell growth. Together, these results suggest that the effects of AR N-C interactions may not always correlate with similar effects on AR-mediated transactivation and/or AR-mediated cell growth. Therefore, drugs designed by targeting AR N-C interaction as a therapeutic intervention for prostate cancer treatment may face unpredictable in vivo effects.
早期报告显示，雄激素受体（AR）的氨基末端和羧基末端（N-C）相互作用对于AR的完整功能很重要。然而，这些相互作用对AR体内效应的影响仍不清楚。在此，我们测试了一些与AR相关的肽和共调节因子，以确定它们对AR N-C相互作用、AR反式激活以及AR共调节因子功能的影响。结果表明，AR共激活因子如ARA70N、凝溶胶蛋白、ARA54和SRC-1可以增强AR反式激活，但对N-C相互作用显示出不同的影响。相反，AR共抑制因子ARA67和Rad9可以抑制AR反式激活，其中ARA67增强而Rad9抑制AR N-C相互作用。此外，与配体结合的AR羧基末端相关肽可以阻断AR N-C相互作用，但只有选择性肽可以阻断AR反式激活和共调节因子功能。我们发现，在5α-二氢睾酮存在的情况下，所有测试的肽都可以在不同程度上抑制前列腺癌LNCaP细胞的生长，但只有含FXXLF的测试肽，而不是含FXXMF的肽，可以抑制前列腺癌CWR22R细胞的生长。总之，这些结果表明，AR N-C相互作用的效应可能并不总是与对AR介导的反式激活和/或AR介导的细胞生长的类似效应相关。因此，以AR N-C相互作用为靶点设计的用于前列腺癌治疗的药物可能面临不可预测的体内效应。
