Akt磷酸化Prohibitin介导其线粒体转位促进膀胱癌的增殖

项目名称： Akt磷酸化Prohibitin介导其线粒体转位促进膀胱癌的增殖

项目编号： No.81472385

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 刘卓炜

作者单位： 中山大学

项目金额： 75万元

中文摘要： 膀胱癌是泌尿系统最常见的恶性肿瘤之一，但是膀胱癌发生及进展机制目前尚未清楚。Prohibitin(PHB)具有抑制增殖作用，一直被认为是肿瘤抑制基因。但是，本实验室发现，在膀胱癌患者的癌组织中PHB表达上调；深入研究显示，Akt通过磷酸化PHB上的丝氨酸来介导表达上调的PHB定位于线粒体内膜。使用PI3K/Akt通路抑制剂抑制Akt的活性可以去除PHB蛋白内丝氨酸位点被磷酸化，也同时促使线粒体内的PHB向细胞核内转移，导致细胞增殖被抑制。由此，我们提出假设：Akt磷酸化PHB介导其线粒体转位并促进膀胱癌细胞增殖。本项目拟采用免疫共沉淀、位点突变、激酶分析等手段以及大量分析膀胱癌的临床样本，获得Akt 直接磷酸化PHB介导其嵌入线粒体的可靠证据。建立体外细胞模型和原位膀胱移植瘤动物模型，揭示PHB促进肿瘤发生发展的机制，为确立PHB 作为膀胱癌预后指标和治疗新靶点提供科学依据。

中文关键词： C13_膀胱肿瘤；蛋白激酶Akt；Prohibitin；线粒体；磷酸化

英文摘要： Bladder cancer is one of the most common cancer, but the carcinogenesis and progression of bladder cancer is not clear. Prohibitin (PHB) can inhibit cell proliferation, has been considered to be a tumor suppressor gene. However we find PHB is overexpressed in bladder cancer. Furthermore, Akt phosphorylate PHB on serine to up-regulate the expression of PHB, which is localized in the inner mitochondrial membrane. The inhibiton of PI3K/Akt pathway can remove the serine phosphorylation of PHB and promote the mitochondrial PHB translocation to nucleus, and inhibit the proliferation of bladder cancer cells. We hypothesize that Akt phosphorylates PHB to mediate its mitochondrial localization and promote the proliferation of bladder cancer cells. In this project we plan to obtain reliable evidence of Akt phosphorylating PHB mediated its insertion into mitochondria, by using immunoprecipitation, mutation, kinase analysis method , and analysis of clinical data of bladder cancer. Futhermore we paln to reveal the mechanism of PHB in the promotion of tumor progression by establishment of in vitro cell model and in situ bladder tumor animal model. Our study will provide the scientific basis for the establishment of PHB as a new prognostic marker and treatment target for bladder cancer.

英文关键词： Bladder cancer;Akt;Prohibitin;mitochondria;phosphorylate