自噬在维持细胞稳定方面起关键作用，是肿瘤细胞产生耐药的重要途径。我们前期研究证实自噬参与前列腺癌细胞产生去势抵抗CRPC的过程，同时前列腺癌特异性膜抗原PSMA在产生CRPC的过程中对自噬起到促进作用，而在常规培养条件下抑制细胞自噬。PSMA在不同环境中对自噬的调控呈相反的机制不明。我们前期研究证实PSMA可激活PI3K/AKT通路，泛素参与PSMA激活AKT的过程。而E3泛素连接酶TRAF6可促进AKT的磷酸化，TTC3可降解p-AKT。结合mTOR是抑制细胞自噬的关健通路，我们推测：PSMA在不同环境中可通过TRAF6和TTC3对PI3K/AKT/mTOR通路进行调节，从而调控前列腺癌细胞的自噬以产生CRPC。本项目拟在前期基础上对CRPC产生过程中的机制进行研究,增强或抑制PSMA、AKT、TRAF6、TTC3及mTOR，通过免疫共沉淀、免疫印记、银染质谱分析、电镜等技术来验证假设。

Autophagy has a critical role in maintaining cell stability, and is an important way of tumor cells drug resistance. Our previous studies have confirmed the participation of autophagy during the generation of castration-resistant prostate cancer (CRPC), while PSMA prostate specific membrane antigen (PSMA) in the generation of the CRPC play a catalytic role for autophagy, and under normal culture conditions inhibiting autophagy. The opposite mechanism of PSMA in different environments on the regulation of autophag is unclear. We confirmed PSMA could activate PI3K/AKT/mTOR pathway, ubiquitination involved in the activation of AKT phosphorylation by PSMA. E3 ubiquitin ligase TRAF6 promotes phosphorylation of AKT, while TTC3 degrades phosphorylated AKT. Combined mTOR is a key inhibition pathway of autophagy, we hypothesized that: PSMA in different environments can adjusted PI3K/AKT/mTOR pathway by TRAF6 and TTC3, thereby regulating autophagy in prostate cancer cells to produce CRPC. On the basis of preliminary studies, the project intends to focuse on the mechanism of CRPC generation, through enhance or inhibit PSMA, AKT, TRAF6, TTC3 and mTOR, co-IP, immunoblotting, silver staining, mass spectrometry and electron microscopy techniques to verify the hypothesis.