探索nMRP1调控粘液表皮样癌多药耐药性的新机制：nGSH/p38MAPK通路

项目名称： 探索nMRP1调控粘液表皮样癌多药耐药性的新机制：nGSH/p38MAPK通路

项目编号： No.81502338

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： 蔡卜磊

作者单位： 中国人民解放军第四军医大学

项目金额： 18万元

中文摘要： 谷胱甘肽（GSH）是细胞内最主要的还原剂和解毒剂。之前认为GSH主要通过自由扩散改变其在细胞内的分布，但近年却发现细胞核内的谷胱甘肽(nGSH)可以逆浓度升高，其具体机制尚不清楚。细胞内GSH含量的改变可以激活p38MAPK通路，影响肿瘤细胞的凋亡和耐药，而多药耐药相关蛋白（MRP1）作为GSH的主要转运蛋白，可能正是调节GSH在细胞内含量和分布的关键。本课题组发现细胞核内的MRP1（nMRP1）可导致粘液表皮样癌（MEC）细胞核内活性氧簇的减少和ABCB1基因启动子活性的增加。我们推测nMRP1将细胞质内的GSH逆浓度转运至细胞核激活了p38MAPK通路,从而导致MEC细胞的凋亡抑制和ABCB1基因启动子活性的增强，最终导致MEC细胞耐药。本项目将从分子、细胞、动物和临床标本四个层面深入分析nMRP1对nGSH/p38MAPK通路的作用机制，为MEC的治疗提供新的药物作用靶点。

中文关键词： 谷胱甘肽；粘液表皮样癌；多药耐药相关蛋白；多药耐药

英文摘要： As the most important reducing agent and antidote in the cells, glutathione (GSH) was thought to distribute through diffusion. But the latest research showed that the nuclear GSH (nGSH) could increase against the concentration gradient. The mechanism of GSH transportation is unclear yet. The alteration of GSH content in the cells could activate p38MAPK pathway and affected apoptosis and chemoresistance of tumor cells. Multidrug resistance-related protein 1 (MRP1), as the main transporter of GSH, is possible the key molecular modulating the content and distribution of GSH in the cells. In our previous study, we found the nuclear MRP1 (nMRP1) could decrease reactive oxygen species (ROS) in the nuclei and enhance the activity of ABCB1 promoter in the mucoepidermoid carcinoma (MEC) cells. According to our results, we speculated that the transportation of GSH from cytoplasm to nuclei by nMRP1 might enhance the activity of ABCB1 promoter and suppress the apoptosis through activating p38MAPK pathway. In this project, we will deeply study the mechanism of how nMRP1 contributes to the multidrug-resistance of MEC cells through nGSH/p38MAPK pathway and provide clues in developing new treatment modalities of MEC.

英文关键词： Glutathione;Mucoepidermoid carcinoma;Multidrug resistance-related protein 1;Multidrug-resistance