以哇巴因为探针药物的肿瘤细胞分子伴侣介导的自噬信号转导途径研究

项目名称： 以哇巴因为探针药物的肿瘤细胞分子伴侣介导的自噬信号转导途径研究

项目编号： No.81503111

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 夏明钰

作者单位： 沈阳药科大学

项目金额： 17.9万元

中文摘要： 自噬是目前抗肿瘤药物研究热点之一。近年研究表明，分子伴侣介导的自噬（CMA）在多种肿瘤中水平明显升高，与肿瘤细胞增殖密切相关，可能成为抗肿瘤药物新的作用靶点。但尚未见抑制肿瘤细胞CMA药物，而CMA信号转导途径亦不十分清楚。本课题组前期研究表明，强心苷类化合物哇巴因在nM浓度即对肿瘤细胞CMA具有明显抑制作用。哇巴因的作用靶点为Na+/K+-ATPase，其下游信号转导通路是强心苷类化合物抗肿瘤作用机制中的焦点。根据前期结果及文献研究，我们推测Na+/K+-ATPase及其下游的ROS-Src-Ras-Raf-ERK信号通路可能对肿瘤细胞CMA具有调控作用。在本项目中我们将以哇巴因为探针药物对上述推测进行研究，旨在阐明Na+/K+-ATPase相关的肿瘤细胞CMA新的信号转导机制及强心苷类化合物新的作用机制，为抗肿瘤药物开发提供重要科学依据。

中文关键词： 哇巴因；分子伴侣介导的自噬；Na+/K+ATPase；活性氧；ERK

英文摘要： Autophagy has become a hot point in the mechanism study of anti-tumor drugs mainly focusing on macroautophagy nowadays. However, recent study demonstrated that chaperone-mediated autophagy (CMA) was up-regulated in different types of cancer cells regardless of the status of macroautophagy, and might be a promising target of anticancer drugs. But chemical modulation of CMA is not currently possible, owing in part to the lack of information on the signaling mechanisms that modulate this pathway. Our previous study showed that cardiac glycoside ouabain, a Na+/K+-ATPase inhibitor, potently inhibited CMA in tumor cells. Na+/K+-ATPase is regarded as a receptor for cardiac glycoside, Na+/K+-ATPase and its down-stream signaling pathway has been shown to be important in the anti-tumor effect of cardiac glycoside. Thus, basing on our previous results and references we speculated that Na+/K+-ATPase and its down-stream ROS-Src-Ras-Raf-ERK pathway may regulate CMA in tumor cells, and this hypothesis will be well explored in this project. The results will benefit the clarification of Na+/K+-ATPase-related CMA signaling pathway in tumor cells, and will also provide a sound basis for the development of new anticancer drugs.

英文关键词： ouabain;chaperone-mediated autophagy;Na+/K+ATPase;ROS;ERK