RIP1在三阴乳腺癌中对TRAIL受体介导的细胞自噬调控机制研究

项目名称： RIP1在三阴乳腺癌中对TRAIL受体介导的细胞自噬调控机制研究

项目编号： No.81202095

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学2

项目作者： 张鹏

作者单位： 华中科技大学

项目金额： 24万元

中文摘要： 三阴乳腺癌是近几年提出的一类特殊乳腺癌亚型，与其它类型乳腺癌相比具有侵袭性高、易转移复发等特点，目前仍缺乏有效的分子靶向治疗手段。申请者前期研究发现，肿瘤坏死因子相关凋亡诱导配体（TRAIL）能激活三阴乳腺癌细胞内保护性自噬。阻断自噬能增强TRAIL的肿瘤杀伤效应，同时特异性诱导受体相互作用蛋白1（RIP1）降解。不仅如此，直接下调RIP1同样能提高三阴乳腺癌细胞对TRAIL诱导凋亡的敏感性，但其具体分子机制尚未明确。基于以上背景，申请者首次提出RIP1参与调控TRAIL受体介导的保护性自噬，并将利用基因组学及蛋白质组学方法展开研究。以RIP1 相互作用蛋白及其调控网络作为研究切入点，揭示RIP1 作为调节蛋白在保护性自噬中的作用、阐明细胞自噬与泛素-蛋白酶体途径之间的调控机制。在完善自噬理论基础上为三阴乳腺癌靶向治疗提供新策略。

中文关键词： 三阴乳腺癌；保护性自噬；细胞凋亡；受体相互作用蛋白1；分子靶向治疗

英文摘要： Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is clinically negative for expression of estrogen and progesterone receptors (ER/PR) and HER-2 protein. It is characterized by its unique molecular profile, highly aggressive behavior, distinct patterns of metastasis, and lack of targeted therapies. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an attractive candidate for cancer therapy because it triggers the extrinsic and/or intrinsic pathway of apoptosis in a variety of tumor cells by engaging the death receptors DR4 and DR5, while sparing most normal cells. However, recent findings show that death receptor can also transmit alternative necroptotic or autopahgy signaling, depending on the cell type and stimulus. Moreover, receptor interacting protein 1 (RIP1) plays an important role in regulation of different types of cell death-mediated by death receptor activation. In our previous study we found that TRAIL can initiate protective autophagy in TNBC cells. Blocking autophagy can induce the selective protein degradation of RIP1 and increase tumor cell sensitivity to TRAIL-induced apoptosis. Furthermore, down-regulating the expression of RIP1 can also enhance the tumuricidal activity of TRAIL against TNBC cells. These results suggest that RIP1 involve in the TRAIL-rece

英文关键词： triple-negative breast cancer；protective autophagy；apoptosis；receptor interacting protein 1；molecular targeted therapy