质子泵抑制剂下调ATP6V1A抑制自噬影响胃腺癌多药耐药的机制研究

项目名称： 质子泵抑制剂下调ATP6V1A抑制自噬影响胃腺癌多药耐药的机制研究

项目编号： No.81472756

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： 邹晓平

作者单位： 南京大学

项目金额： 65万元

中文摘要： 胃癌化疗耐药的问题日益严重并亟待解决。由于自噬在抗肿瘤治疗中是否起着细胞保护作用仍不明确，因此基于抑制自噬逆转化疗耐药的肿瘤治疗策略是否能带来临床受益仍需进一步探究。我们发现临床常用的质子泵抑制剂预处理能增强胃癌对顺铂的敏感性，推测与干预自噬有关。由于自噬依赖溶酶体膜上空泡型质子泵(Vacuolar H+-ATPase)维持的酸性微环境，因此我们推测:质子泵抑制剂是否通过某种转录调控机制下调编码空泡型质子泵V1亚基A结构域的ATP6V1A表达，干扰了溶酶体膜内外酸性微环境而阻断保护性自噬，进而通过内质网应激导致细胞凋亡以达到化疗增敏的目的？本研究通过一系列体内外实验明确：ATP6V1A的转录调控机制，质子抑制剂如何以其为靶点阻断自噬，并经未折叠蛋白反应中IRE1α、PERK、ATF6信号通路启动下游Bcl-2、BAX等凋亡信号促使细胞凋亡，为质子泵抑制剂逆转胃腺癌多药耐药提供理论依据。

中文关键词： C07_胃肿瘤；多药耐药；自噬；空泡型质子泵

英文摘要： Chemotherapy Multi-drug resistance of gastric adenocarcinoma is increasingly becoming a serious problem needed to be solved. Whether autophagy plays as a cytoprotective or cytotoxic role in anti-cancer therapy is still undefined. So, it needs to be further investigated if strategy of autophagy suppression might reverse multi-drug resistance and have therapeutic benefit in the clinical treatment of cancer. We have found the widely used Proton Pump Inhibitors will increase cytotoxicity of Cisplatin when combine with it although the mechanism is not yet clear. Autophagy, which is an important compensatory mechanism in endoplasmic reticulum stress, depends on the acidic microenvironment maintained by Vacuolar H+-ATPase on lysosomal membrane. For this reason, we hypothesise that Proton Pump Inhibitors will block the autophagy flux by inhibiting lysosomal ATP6V1A through some kinds of transcriptional regulatory mechanism and disturbing lysosomal acidic microenvironment, induce apoptosis by enhanced endoplasmic reticulum stress finally. This study aimed to explore the follow contents: the transcriptional regulatory mechanism of ATP6V1A, and if proton pump inhibitor might inhibit autophagy flux by targeting ATP6V1A, due to induced cell apoptosis possibly by enhance endoplasmic reticulum stress and by the regulation of IRE1α, PERK, ATF6 in unfolded protein response,and Bel-2, BAX at downstream of this signal path. Our study is designed to demonstrate that Multi-drug resistance of gastric adenocarcinoma cell line to cisplatin will be reversed by Proton Pump Inhibitor as an autophagy inhibitor.

英文关键词： Gastric Adencarcinoma;Muilt-drug Resistance;Autophagy;Vacuolar Proton Pump