雄激素剥夺治疗是晚期转移性前列腺癌的主要治疗方法。但在治疗过程中，前列腺癌从激素依赖演变为去势抵抗状态，分子机理尚未完全明了。我们前期研究发现，除热休克蛋白分子外，线粒体外膜蛋白TOMM20参与了维持AR蛋白稳定性。抗雄激素药物促进了AR和TOMM20蛋白质降解，继而升高了细胞ROS水平。据此我们提出如下科学假说：抗雄激素药物经AR-TOMM20途径激活了线粒体介导的细胞生存和抗凋亡相关信号分子，导致前列腺癌细胞产生抗雄激素药物抵抗。本项目拟从以下三个方面进行研究：①揭示线粒体外膜蛋白TOMM20抑制前列腺癌发展的作用。②明确AR和TOMM20蛋白质互作的结构域，研究功能上的相互影响。③阐明TOMM20阻止前列腺癌产生抗雄激素药物抵抗的分子机制。本项目将揭示线粒体外膜蛋白TOMM20稳定AR蛋白的新机制，为发展新的治疗策略克服抗雄激素药物抵抗提供实验依据，具有很好的理论创新和临床应用价值。

Androgen deprivation therapy is the mainstay of treatment for the advanced and metastatic prostate cancer (PCa). However, PCa patients develop drug resistance and transit to the castration-resistant prostate cancer in the course of treatment. The molecular mechanism is not clearly defined. Our recent studies demonstrated that in addition to HSP molecules, AR protein is co-localized with mitochondrial outer membrane protein TOMM20, and physically interact to maintain the reciprocal protein stability. The anti-androgen agents induced the degradation of AR and TOMM20 proteins, thereby elevated ROS level. We hypothesized that the anti-androgen agents activated the mitochondria-mediated cell survival or anti-apoptotic signals by destroying TOMM20 protein and producing ROS, thereby promoted the development of resistance to anti-androgen agents. To test these hypotheses, we will pursue the following three tasks: 1. To determine the roles of TOMM20 in the progression of prostate cancer. 2. To identify the interactive protein domains of AR and TOMM20, and analyze the mutual functional influence in the AR-positive PCa cells. 3. To define the roles of TOMM20 in the development of resistance to anti-androgen agents. The proposed project will identify the novel roles of TOMM20 in the maintenance of AR protein stability independent of HSP molecules, and explicit how TOMM20 inhibits the progression of prostate cancer and the resistance to anti-androgen agents. The implementation of this project will help to develop novel strategies to overcome the resistance of PCa patients to anti-androgen agents, showing great theoretical innovation and clinical value.