PRIMA-1MET诱导p53突变型肺癌细胞自噬的分子机制及其与凋亡的相关性研究

项目名称： PRIMA-1MET诱导p53突变型肺癌细胞自噬的分子机制及其与凋亡的相关性研究

项目编号： No.81201779

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1

项目作者： 熊华

作者单位： 华中科技大学

项目金额： 23万元

中文摘要： 临床上约有50%肺癌p53发生突变。作为最重要的抑癌基因，p53突变导致其促凋亡功能丧失，是肿瘤逃避常规治疗的一个关键因素。目前针对p53突变肺癌仍缺乏有效的治疗手段。前期研究中，我们利用小分子化合物PRIMA-1MET特异性恢复突变p53的野生型功能，促使p53突变型肺癌细胞发生凋亡，并首次发现该过程中细胞自噬明显增强，但其具体机制不明。研究认为除凋亡外，p53也参与调控自噬，后者与细胞凋亡密切相关。但是自噬调控机制的复杂性及其双重作用使得如何确切评价p53介导的自噬在抗肿瘤治疗中的作用已成为自噬研究的热点和难点。本课题以p53突变型肺癌细胞为研究模型，利用PRIMA-1MET的特异性作用，深入剖析PRIMA-1MET作用于突变p53导致细胞自噬的分子机制，探讨自噬与凋亡相关联的可能信号通路。本研究旨在通过全面设计和层层分析，为直接靶向治疗p53突变型肺癌提供新的理论基础。

中文关键词： p53突变；自噬；凋亡；PRIMA-1Met；

英文摘要： It has been reported that somatic mutations p53 were frequently found in 50% of lung cancer. As one of the most important tumor suppressor genes, mutant p53 is associated with impaired programmed cell death(apoptosis) induced by common treatment. To effective and selective killing of lung cancer harboring mutant p53 would be an ideal strategy for intense interest. In our previous data, we utilized PRIMA-1MET, a small molecular, restored wildtype p53 function to mutant p53 and induced massive apoptosis in lung cancer cells as expected. Meanwhile, it dramatically initiated autophagy,a basic physiological activity. But the precise mechanism for autophagy induction remains unknown. As we may know, p53 has been elucidated to induce autophagy, with stongly crosstalk to apoptosis. So far how to evaluate the complicated effect for autophagy on p53-dependent antitumor treatment needs to be dissected. Herein, based on previous data, our present project utilize PRIMA-1MET as a modulator to induce apoptosis and autophagy in lung cancer with mutant p53. Furthermore, we will utilize multiple research strategies to address precise molecular mechanism of p53-initiated autophagy on apoptosis, generating some novel clues for targeting lung cancer in particular with p53 mutation.

英文关键词： mutant p53；autophagy；apoptosis；PRIMA-1Met；