PrLZ调控AMPK信号抑制自噬促进前列腺癌化疗抵抗的机制研究

多西他赛紫杉醇类化疗是各国指南新近强烈推出对晚期去势抵抗性前列腺癌(CRPC)患者可以延长生存时间的标准治疗方法之一，但仅仅3-6月就出现化疗抵抗，患者最终死亡，其调控分子机制不清。本项目在前期研究中发现高表达PrLZ可抵抗多西他赛诱导的前列腺癌(PCa)细胞凋亡，抑制细胞自噬形成，伴随着AMPK信号的激活，特异性敲除PrLZ可恢复PCa对化疗药敏感性这一现象基础上，提出“PrLZ介导的AMPK信号可能通过调控自噬形成是PCa化疗抵抗的重要原因之一”科学假设。本项目以不同表达PrLZ的PCa多西他赛化疗抵抗细胞模型、PCa化疗耐药裸鼠皮下和原位模型、及PrLZ特异性敲除TRAMP前列腺癌小鼠模型为研究对象，模拟PCa疾病进展和临床化疗耐药过程，观察 PrLZ对自噬及其关键信号影响和化疗抵抗之间关系，揭示其调节的确切分子机制，探索化疗联合靶向调控自噬对抑制PCa进展的新策略。

Docetaxel-mediated chemotherapy is one of the standard strategies for the late stage of the castration resistance prostate cancer (CRPC). It prolongs the 3-6 months overall survival for the late stage patients, however, most of patients eventually developed into chemo-resistance stage, and the detailed molecular mechanisms are unclear. Our preliminary data showed that over-expression of PrLZ in prostate cancer cells could inhibit docetaxel-mediated apoptosis, and also activation of AMPK signals and inhibit the cell autophagy simultaneously. While specific knocking-down the expression of PrLZ will reverse the chemo-sensitive in prostate cancer cells. Base on those data, we proposed that PrLZ-mediated AMPK signaling may be one of the important causes for prostate cancer chemo-resistance by regulating autophagy. In present project, we will analyze the role of PrLZ between autophagy and chemo-resistance by using docetaxel-resistant prostate cancer cell models, prostate cancer subcutaneous and in situ nude mice models, and PrLZ-specific knockout TRAMP prostate cancer mouse models. We also try to dissect the detailed molecular mechanisms of PrLZ in autophagy and chemo-resistance, and also try to figure out the new strategy for targeting prostate cancer via binding chemotherapy and autophagy manipulation.