Lin Hui-Kuan, Altuwaijri Saleh, Lin Wen-Jye, Kan Pu-Yeh, Collins Loretta L, Chang Chawnshang
George Whipple Laboratory for Cancer Research, Department of Pathology, University of Rochester Medical Center, Rochester, New York 14642, USA.
J Biol Chem. 2002 Sep 27;277(39):36570-6. doi: 10.1074/jbc.M204751200. Epub 2002 Jul 15.
Upon binding to androgen, the androgen receptor (AR) can translocate into the nucleus and bind to androgen response element(s) to modulate its target genes. Here we have shown that MG132, a 26 S proteasome inhibitor, suppressed AR transactivation in an androgen-dependent manner in prostate cancer LNCaP and PC-3 cells. In contrast, MG132 showed no suppressive effect on glucocorticoid receptor transactivation. Additionally, transfection of PSMA7, a proteasome subunit, enhanced AR transactivation in a dose-dependent manner. The suppression of AR transactivation by MG132 may then result in the suppression of prostate-specific antigen, a well known marker used to monitor the progress of prostate cancer. Further mechanistic studies indicated that MG132 may suppress AR transactivation via inhibition of AR nuclear translocation and/or inhibition of interactions between AR and its coregulators, such as ARA70 or TIF2. Together, our data suggest that the proteasome system plays important roles in the regulation of AR activity in prostate cancer cells and may provide a unique target site for the development of therapeutic drugs to block androgen/AR-mediated prostate tumor growth.
与雄激素结合后，雄激素受体（AR）可转运至细胞核并与雄激素反应元件结合，以调节其靶基因。在此我们表明，26S蛋白酶体抑制剂MG132在前列腺癌LNCaP和PC-3细胞中以雄激素依赖的方式抑制AR反式激活。相比之下，MG132对糖皮质激素受体反式激活无抑制作用。此外，蛋白酶体亚基PSMA7的转染以剂量依赖的方式增强AR反式激活。MG132对AR反式激活的抑制可能会导致前列腺特异性抗原的抑制，前列腺特异性抗原是用于监测前列腺癌进展的一种知名标志物。进一步的机制研究表明，MG132可能通过抑制AR核转运和/或抑制AR与其共调节因子（如ARA70或TIF2）之间的相互作用来抑制AR反式激活。总之，我们的数据表明蛋白酶体系统在前列腺癌细胞中AR活性的调节中起重要作用，并且可能为开发阻断雄激素/AR介导的前列腺肿瘤生长的治疗药物提供一个独特的靶点。
