DJ-1蛋白氧化态修饰方式在抗肿瘤化合物诱导肿瘤细胞自噬/凋亡转化中的作用研究

项目名称： DJ-1蛋白氧化态修饰方式在抗肿瘤化合物诱导肿瘤细胞自噬/凋亡转化中的作用研究

项目编号： No.81202558

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 应美丹

作者单位： 浙江大学

项目金额： 24万元

中文摘要： 自噬和凋亡是两种不同的程序性死亡方式，均在抗肿瘤药物的疗效中发挥了重要影响。最新报道某些抗肿瘤药物在不同浓度下可分别引起肿瘤细胞发生自噬或凋亡，但"自噬/凋亡间的转化机制"尚不明确，已经成为研究热点之一。我们在前期研究中已证实以氧化应激为抗肿瘤机理的候选药物Fenretinide和已确认有效的抗肿瘤新型化合物MSFTZ呈现浓度依赖式地诱导肿瘤细胞发生自噬或者凋亡，且此关系与细胞内氧化程度密切相关；进一步的研究发现，氧化应激调控蛋白DJ-1可能是肿瘤细胞自噬/凋亡间转化的关键蛋白。本项目将在此基础上，深入研究DJ-1蛋白氧化态改变形式与肿瘤细胞自噬/凋亡间转化的相互关系及其分子机制，阐明内质网应激信号通路多层次调控的内涵本质，旨在从氧化应激角度诠释自噬/凋亡间转化的生命本质，力求发现新的生命现象，为发展以DJ-1蛋白及其下游内质网应激信号通路关键蛋白作为靶点的抗肿瘤创新药物奠定理论基础。

中文关键词： 自噬；凋亡；氧化应激；DJ-1；氧化态修饰

英文摘要： There are two major types of programmed cell death, apoptotic cell death and autophagic cell death, both of which influence the anti-tumor effect of chemotherapeutic agents. Recent studies report that some anti-cancer agents can induce autophagy as well as apoptosis in cancer cells, however, the functional relationship between apoptosis and autophagy is unclear. It is less clear, however, by which mechanism anti-cancer agents accurately trigger the switch between autophagy and apoptosis. We report here that Fenretinide and MSFTZ, two anti-cancer agents with the ability to induce cell death by elevating oxidative stress, induce autophagy or apoptosis under different concentrations in cancer cells, and the switch between autophagy and apoptosis induced by Fenretinide and MSFTZ was highly related to the process of oxidative stress. Moreover, DJ-1, a key factor of oxidative stress process, may play an important role in controlling the switch by its different oxidative modifications. Therefore, we will further investigate the role of DJ-1 and its different oxidative modifications in the switch between autophagy and apoptosis induced by Fenretinide or MSFTZ driven oxidative stress, and in the hope to provide a new insight for the switch between autophagy and apoptosis and advance the development of a new therapeutic s

英文关键词： AUTOPHAGY；APOPTOSIS；OXIDATIVE STESS；DJ-1；OXIDATIVE MODIFICATION