胰蛋白酶抑制剂BBI通过RIP3激活线粒体途径诱导肿瘤细胞凋亡的机制研究

项目名称： 胰蛋白酶抑制剂BBI通过RIP3激活线粒体途径诱导肿瘤细胞凋亡的机制研究

项目编号： No.31271476

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 龙民慧

作者单位： 天津科技大学

项目金额： 80万元

中文摘要： 胰蛋白酶抑制BBI可通过诱导肿瘤细胞凋亡发挥其抗肿瘤作用，对正常组织和细胞毒害作用不明显，其机理尚未明确。RIP3广泛表达于正常组织，未见在肿瘤中表达。我们前期研究发现绿豆BBI能诱导肿瘤细胞表达RIP3，抑制Bcl-2 转录，促进Bax转录，促使cyt-c释放到细胞质中，激活caspase3、caspase9，但不影响Fas/Fas配体转录，不能活化caspase8，结果提示绿豆BBI可能通过RIP3介导激活细胞凋亡的线粒体途径导致肿瘤细胞凋亡；动物实验还证实绿豆BBI能抑制小鼠的肿瘤生长。本研究拟通过分析绿豆BBI处理后肿瘤细胞中RIP3及细胞凋亡线粒体途径中信号分子的表达、激活等情况，结合动物模型和基因芯片找出BBI激活RIP3表达对肿瘤细胞凋亡通路的影响，阐明RIP3调控肿瘤细胞凋亡的线粒体途径和BBI抗肿瘤机制，为临床提供新的预后指标，为抗肿瘤药物研发提供新的治疗靶点和新思路。

中文关键词： BBI；RIP3；线粒体途径；细胞凋亡；动物模型

英文摘要： Bowman-birk trypsin inbitor BBI has been shown to have anticarcinogenic effects on many different cell lines for its induction of apoptosis, but the biochemical and molecular bases for this mechanism of action need to be further elucidated. The capacity of BBI for inducing RIP3 expression, increasing the transcription of Bax, decreasing the level of Bcl-2 mRNA and little influencing on the Fas/FasL mRNA has also been demonstrated in our previous study. We applied Western-blot assay to further detect the role of Mung bean BBI on tumor cell apoptosis, and the result confirmed that Mung bean BBI enhanced the releasing of cytochrome C from mitochondria as well as markedly induced the activation of caspase3, Caspase9 and caspase8. Our previous result suggested that the apoptosis induced by Mung bean BBI was correlated with mitochondrial dysfunction. Mung bean BBI has also been evidenced by inhibiting the growth of tumor in tumor bearing mice model in our animal experiment. So，we proposed that the possible mechanism of mung bean BBI anti-cancer properties is via mitochondrial apoptosis signal path: 1, BBI may activate the transcription and expression of tumor RIP3 gene, subsequently RIP3 directly triggers signals of mitochondrial apoptosis pathway; 2, the expression of RIP3 in tumor cells may negatively regulate PI3K-

英文关键词： BBI；RIP3；Mitochondrial pathway；apoptosis；animal model