苦瓜凝集素诱导肝癌细胞凋亡的分子机制

项目名称： 苦瓜凝集素诱导肝癌细胞凋亡的分子机制

项目编号： No.81201717

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： 张志毅

作者单位： 中山大学

项目金额： 23万元

中文摘要： 寻找抗肿瘤中药有效成分及其作用机制是目前研究热点和难点之一。我们前期发现苦瓜凝集素（MCL），一种自行从中药苦瓜子中提纯的单一成分，显著抑制肝癌细胞生长。进一步实验表明MCL上调Fas，降低线粒体跨膜电位，并激活H2AX和 caspase 8/9，提示MCL引起DNA损伤及细胞凋亡，但其具体分子机制尚未清楚。本项目拟采用一系列分子细胞生物学及免疫学实验技术，利用Bak和/或Bid缺失细胞模型和裸鼠模型，在蛋白表达调控及细胞功能上阐明MCL抑制肝癌细胞生长的分子机制，寻找MCL的作用靶点，揭示MCL引起DNA损伤的作用及其机理，探讨MCL激活Fas和线粒体凋亡信号转导通路的分子机制，明确MCL诱导的DNA损伤与细胞凋亡的相互影响，从而获得MCL抑制肝癌细胞生长的可靠证据，为MCL治疗肝癌的临床研究奠定坚实基础，并为诠释中草药有效成分治疗肿瘤提供充分的科学依据。

中文关键词： 苦瓜凝集素；Bid；细胞凋亡；肝细胞癌；

英文摘要： Utilizing active ingredient of Chinese herbal medicine to tumor treatment has been currently attracting more and more interest. Lately, we found that Momordica Charantia Lectin (MCL), a component purified from traditional Chinese herb bitter gourd, significantly inhibited cell growth. Further study revealed that MCL exposure in hepatocellular carcinoma (HCC) resulted in Fas upregulation, decline of mitochondrial membrane potential, and activation of H2AX and caspase 8/9.These findings indicated that MCL induced DNA damage and apoptosis in HCC. However, the detailed mechanism remains elusive. In this study, we aim to, in vitro and in vivo, elucidate the mechanism through which MCL induces growth inhibition, to quest for the molecular target of MCL, to disclose the mechanism of MCL-mediated DNA damage response, and to investigate the mechanism via which MCL activates the Fas-dependent and mitochondria-dependent apoptotic pathways, using a series of biomolecular and immunological experiments in Bak-/- and/or Bid-/- cell and animal models. Likely, our study will provide not only solid evidence that MCL is capable of inhibiting cell growth in HCC, but also a scientific basis for HCC chemotherapeutic treatment mediated by active ingredient extracted from traditional Chinese Medicine.

英文关键词： momordica charantia lectin；apoptosis；Bid；hepatocellular carcinoma；