异莲心碱靶向NF-κB信号通路关键转录因子p65诱导肝癌细胞凋亡的机制

项目名称： 异莲心碱靶向NF-κB信号通路关键转录因子p65诱导肝癌细胞凋亡的机制

项目编号： No.31301147

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： 舒广文

作者单位： 中南民族大学

项目金额： 23万元

中文摘要： 肝癌是严重威胁人类健康的恶性肿瘤，但现有药物疗效并不理想。异莲心碱是传统药材莲心的主要化学组分之一，目前对其在抗肿瘤方面的活性缺乏系统的研究。项目申请人前期工作发现，它在体外和裸鼠体内均能显著诱导肝癌细胞凋亡，对非恶性肝细胞毒性很低，有用于肝癌治疗的潜力。异莲心碱能相对选择性地抑制肝癌细胞内转录因子p65的转录激活活性，从而下调NF-κB凋亡抑制信号，促进细胞凋亡。 基于上述工作，为深入探讨异莲心碱抑制p65活性的机理，本项目拟检测异莲心碱对肝癌细胞内p65蛋白亚细胞定位、翻译后修饰以及与辅因子相互作用的影响，确定表达水平、翻译后修饰或功能性相互作用被异莲心碱改变的p65活性调控蛋白，揭示异莲心碱抑制p65活性过程中涉及到的关键性分子事件，阐明其诱导凋亡的作用机理。该工作将丰富对天然小分子靶向NF-κB诱导癌细胞凋亡的认识，并为考虑以异莲心碱为先导化合物开发抗肝癌新药提供理论依据。

中文关键词： 核因子-κB；肝癌；凋亡；；

英文摘要： Hepatocellular carcinoma (HCC) is a kind of malignant tumor which severely threatens public health. However, the clinical outcomes of anti-HCC drugs currently available are not so satisfied. Isoliensinine exists abundantly in the traditional Chinese herb "Lianxin" (lotus plumule). Till now, it remains poorly understood whether isoliensinine exhibits any anti-tumor activity. Our previous investigations revealed that isoliensinine dramatically induced HCC cell apoptosis both in vitro and in nude mice, and showed few toxic effects to untransformed hepatocytes. These observations suggested that isoliensinine has the potential to be applied in HCC treatment. Further studies revealed that isoliensinine was capable of selectively suppressing the transactivity of transcription factor p65 in HCC cells. This event downregulated NF-κB anti-apoptotic signalling and promoted HCC cell apoptosis. Based on these findings, to understand the molecular mechanisms through which isoliensinine suppresses the transactivity of p65, this proposal is planning to explore the effects of isoliensinine on the subcellular localization, post- translational modifications and functional interactions of p65 subunit, identify the p65 transactivity-regulating proteins whose expressional levels, post- translational modifications or functional inter

英文关键词： NF-κB；hepatocellular carcinoma；apoptosis；；