隐丹参酮通过抑制STAT3酪氨酸磷酸化抗恶性神经胶质瘤增殖及其分子机制研究

项目名称： 隐丹参酮通过抑制STAT3酪氨酸磷酸化抗恶性神经胶质瘤增殖及其分子机制研究

项目编号： No.81460619

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 吕良

作者单位： 桂林医学院

项目金额： 48万元

中文摘要： 恶性神经胶质细胞瘤是最常见的中枢神经系统恶性肿瘤，目前尚缺乏有效治疗方法。我们的实验证明了隐丹参酮通过选择性抑制p-STAT3 (Tyr 705)，使STAT3核转位，下游靶蛋白cyclin D1, survivin表达降低，从而显著抑制恶性神经胶质细胞瘤增殖，使细胞阻滞于G0/G1期。在裸鼠原位癌模型中，隐丹参酮也显著延长小鼠生存期。那么，隐丹参酮如何选择性抑制p-STAT3 (Tyr 705)，其分子机制是什么？进一步实验表明，磷酸酶抑制剂正钒酸钠可以逆转隐丹参酮对p-STAT3 (Tyr 705)的抑制，这提示我们隐丹参酮的作用机制可能与磷酸酶有关。本项目拟进一步采用Si RNA、免疫共沉淀和液相串联质谱蛋白测序等方法，旨在获得隐丹参酮负性调控STAT3信号通路的可靠证据并探索其分子机制。本项目有望揭示隐丹参酮抗肿瘤作用的新机制，为开发治疗恶性神经胶质瘤的新途径提供更充分的科学依据。

中文关键词： 抗肿瘤；隐丹参酮；信号的转录因子和活化子3；信号转导；恶性神经胶质瘤

英文摘要： Malignant gliomas (MGs) are the most common cancers in central nervous system, which are lack of effective therapeutic approaches. Our results proved that Cryptotanshinone(CTS) significantly suppressed malignant gliomas cell proliferation, specfictly inhibited p-STAT3 (Tyr 705), accumulation of STAT3 in nuclear was deceased, following the downregulation of STAT3-regulated proteins (cyclin D1, survivin) and the cell cycle arrested in G1/G0 phase. Furthermore, CTS extended survival of nude mice bearing intracerebral U87MG xenograf. In summary, we firstly proposed that CTS maybe a potential anti-proliferation agent via specific inhibition of STAT3 signaling. However, what's molecular mechanism behind CTS? Further experiments showed that phosphatases inhibitor pervanadate reverses the p-STAT3(Tyr 705) inhibitory effect of CTS. These methods of siRNA, immunopre- cipitation and LC-MS/MS and so on were used in order to comfirm that CTS negative regulated STAT3 signal transduction pathway and explore its molecular mechanism. We hope our project reveales the new mechanism of CTS on anti-tumor and backes up to develop new therapeutic intervention for malignant gliomas.

英文关键词： anti-tumor;Cryptotanshinone;STAT3;Signal transduction;Malignant gliomas