内质网应激激活PI3K通路诱导肝癌细胞耐药的分子机制

项目名称： 内质网应激激活PI3K通路诱导肝癌细胞耐药的分子机制

项目编号： No.U1204815

项目类型： 联合基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 翟文龙

作者单位： 郑州大学

项目金额： 30万元

中文摘要： 内质网应激反应是细胞逃避损伤的一种自我保护反应，可诱导肿瘤细胞对化疗药物产生耐药。钙网蛋白属于分子伴侣，可参与内质网应激反应，并可发生膜转位，膜转位后的钙网蛋白与PI3K通路的激活有关。我们前期研究结果显示内质网应激可通过激活PI3K/Akt通路诱导肝癌细胞对阿霉素产生耐药。但内质网应激激活PI3K的分子机制尚不清楚。本研究拟从以下几方面探讨内质网应激是否通过诱导钙网蛋白膜转位来激活PI3K通路，进而引发肝癌细胞对阿霉素耐药：1.检测内质网应激可否诱导肝癌细胞内钙网蛋白发生膜转位及其转位后是否与PI3K发生免疫共沉淀。2.干扰肝癌细胞内钙网蛋白的膜转位，观察它对PI3K通路活化状态的影响。3.检测钙网蛋白膜转位受阻能否逆转内质网应激诱导的肝癌细胞对阿霉素的耐药现象，揭示内质网应激通过诱导钙网蛋白膜转位来激活PI3K通路，引发肝癌细胞对阿霉素产生耐药的机制。

中文关键词： 肝癌细胞；内质网应激；耐药；PI3K/Akt通路；钙网蛋白

英文摘要： Endoplasmic reticulum stress (ERS) could trigger a series of cyto-protective responses and helps the cells escape from being hurt, which renders the tumor cells less sensitive to the chemotherapy. Calreticulin (CRT) is a kind of molecular chaperon and could translocate to the cell membrane, which is associated with the activation of PI3K pathway. Our previous data showed that ERS strikingly activated PI3K pathway and induced chemo-resistance in hepatocellular carcinoma cells. Inhibition of PI3K could partly abrogated ER stress induced chemo-resistance. However, it is not clear about how ERS activates PI3K pathway. We will investigate whether PI3K pathway is activated via CRT translocation upon ERS, which subsequently decreases the sensitivity of hepatocellular carcinoma cells to the chemotherapeutic agent, adrimycin as follows: 1. It will be explored whether ERS could induce CRT translocation and the correlation of CRT translocation and PI3K pathway. 2. CRT translocation will be inhibited or induced to study its effects on the activation of the PI3K pathway. 3. It will be studied whether ERS-induced chemo-resistance will be overcome after inhibition of CRT translocation, which will provides new insights into the molecular mechanism of ERS-induced chemo- resistance in hepatocellular carcinoma cells.

英文关键词： Hepatocellular carcinoma cells；Endoplasmic reticulum stress；drug resistance；PI3K/Akt signaling；calreticulin