glibenclamide通过靶向SUR1-p70S6K调控细胞代谢酶表达抑制非小细胞肺癌作用机制的研究

项目名称： glibenclamide通过靶向SUR1-p70S6K调控细胞代谢酶表达抑制非小细胞肺癌作用机制的研究

项目编号： No.81473241

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王雪融

作者单位： 南京医科大学

项目金额： 65万元

中文摘要： 代谢异常在肿瘤的发生发展中起重要作用，是肿瘤研究的新热点。降糖药为肿瘤治疗提供了新方向。磺脲类降糖药glibenclamide与降低癌症的发病率和死亡率相关，但是关于它抗肿瘤的作用机制却不明确。我们预实验发现glibenclamide可抑制非小细胞肺癌的生长；抑制p70S6K信号通路；调控细胞内代谢酶GLS2、ASNS、HSD17B12的表达；并抑制其受体SUR1的磷酸化和SUR1-p70S6K的结合，提示glibenclamide有抗肿瘤作用。在本课题中，我们将从分子、细胞、整体动物水平，及在人肺癌组织标本上，明确glibenclamide靶向SUR1的抗肿瘤作用，阐明其通过抑制p70S6K信号通路调控细胞内代谢酶表达的作用机制，并探索glibenclamide抑制SUR1磷酸化、SUR1-p70S6K的结合、p70S6K磷酸化和活性的分子基础。为肿瘤诊断提供新指标，为治疗提供新靶点。

中文关键词： 非小细胞肺癌；磺脲受体1；p70S6K；肿瘤代谢；抗肿瘤药物

英文摘要： Targeting cancer metabolism attracts great interests. A novel strategy is the application of oral antidiabetic drugs. Recently, glibenclamide was reported to reduce cancer risk and mortality. However, its effect and mechanism have not been clarified. We found that glibenclamide inhibited the growth, the EMT, and the migration of non-small cell lung carcinoma. Glibenclamide inhibited p70S6K signaling pathway and regulated the metabolic enymes expression, such as GLS2, ASNS, HSD17B12. Moreover, glibenclamide reduced the phosphorylation of SUR1 and p70S6K, and their physical binding. It suggests that glibenclamide exhibits anticancer effects. In this study, we will evaluate the anticancer effect of glibenclamide, clarify its mechanism of interfere p70S6K-regulated metabolic enzymes expression, and explore its inhibitor effects on phosphorylation of SUR1, p70SK6, and their physical binding both in cell lines, animal models, and in human tissue samples. Our findings will suggest new diagnostic markers and therapeutic targets for cancer therapy.

英文关键词： NSCLC;SUR1;p70S6K;cancer metabolism;anticancer drugs