青蒿素衍生物抗肿瘤活性靶点和机制研究

项目名称： 青蒿素衍生物抗肿瘤活性靶点和机制研究

项目编号： No.31301169

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 陈新雅

作者单位： 中国科学院上海有机化学研究所

项目金额： 25万元

中文摘要： 天然活性小分子化合物青蒿素是具有高活性的抗疟首选药物，并具有抗肿瘤活性。但是其作用机制尚未定论。本项目在我们前期工作合成青蒿素衍生物AAD-1/2并筛选到其作用靶点蛋白Lgp1的基础上，拟于细胞水平和动物水平观察小分子对肿瘤生长的影响；通过检测caspase3、PARP、GRP78、CHOP等的表达变化以及eIF2 alpha磷酸化状态和功能的变化，论证AAD-1/2以内质网应激（ER stress）作用方式诱导细胞凋亡的假说；同时对Lgp1进行基因敲除和过表达实验，证实AAD-1/ 2通过Lgp1靶点蛋白影响上述信号通路，揭示AAD-1/2通过靶蛋白Lgp1影响ER-stress进而诱导细胞凋亡这样一种分子信号作用途径，系统阐明其抗肿瘤活性作用机制。

中文关键词： 青蒿素衍生物；筛选鉴定；靶点蛋白；相互作用；信号通路

英文摘要： Artemisinin is a preferred drug with high anti-malarial activity, and have recently been suggested to have anti-cancer effects. However, the mechanisms of its action are still not fully understood. Based on our previous work that we have synthesized artemisinin analogues AAD-1/2 and identified their target protein Lgp1, we intend to investigate the effects of AAD-1/2 on tumor growth. The research will be directed toward examining the expression of caspase3, PARP, GRP78 or CHOP and also the phosphorylation status of eIF2 alpha, in order to test our hypothesis that AAD-1/2 induces apoptosis through ER stress. Otherwise, Lgp1-RNAi and Lgp1 overexpression will be used to confirm that Lgp1 is the target of AAD-1/2 in vivo. Thus, we will uncover a possible novel signaling pathway that AAD-1/2 causes ER stress-induced apoptosis by their interaction with Lgp1 protein, and clearly clarify their anti-tumor mechanism.

英文关键词： artemisinin derivatives；identification；target protein；interaction；cell signaling