核受体TR3/Nur77在子宫颈癌细胞中调控自噬性死亡的机制

项目名称： 核受体TR3/Nur77在子宫颈癌细胞中调控自噬性死亡的机制

项目编号： No.81472425

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： 陈航姿

作者单位： 厦门大学

项目金额： 85万元

中文摘要： 子宫颈癌是严重威胁妇女健康的疾病。由于许多子宫颈癌对p53等抑癌基因介导的细胞凋亡并不敏感，因此寻找不依赖于诱导细胞凋亡的方法治疗子宫颈癌是目前亟需解决的问题。我们的前期结果发现，靶向核受体TR3（也称为Nur77）的化合物THPN能够以TR3依赖的方式诱导细胞发生致死性线粒体自噬。然而子宫颈癌细胞对THPN诱导的自噬并不敏感，TR3诱导线粒体自噬的信号机制也不完全清楚。本项目将在子宫颈癌细胞中研究①Akt是否是抑制THPN诱导的自噬性死亡的上游因子，并明确Akt通过对TR3的磷酸化发挥此功能的作用机制；②分析TR3通过与ANT结合引起线粒体膜电位丧失的分子机理；③阐明LC3结合蛋白调控线粒体自噬的信号转导通路；④寻找促进THPN诱导子宫颈癌细胞发生自噬性死亡的方法。通过研究期望能够阐明线粒体自噬的调控机制，为开发包括THPN在内的特异性诱导子宫颈癌细胞发生自噬性死亡的药物提供理论依据。

中文关键词： C22_宫颈肿瘤；核受体TR3/Nur77；自噬；磷酸化；信号转导

英文摘要： Cervical cancer is a serious threat to women's health. Since many cervical cancers are resistant to tumor suppressor genes such as p53 induced cell apoptosis, it is of great importance and urgency to develop new therapeutic strategies independent of inducing apoptosis for cervical cancer treatment. Our previous data demonstrated that THPN (1-(3,4,5-trihydroxyphenyl)nonan-1-one), a nuclear orphan receptor TR3/Nur77 targeting compound, efficiently induces lethal mitophagy in a TR3/Nur77 dependent manner. However, cervical cancer cell lines are not sensitive to THPN induced autophagic cell death, and the underlining signal transduction pathway still needs to be addressed. Based on the preliminary data, this project will ① demonstrate whether Akt plays as a upstream inhibitory regulator of THPN-induced autophagy via phosphorylating TR3/Nur77 and investigate the underling mechanism, ② study the molecular mechanism of TR3/Nur77 on regulating dissipation of mitochondrial membrane potential via interacting with ANT, ③ analyze the regulatory functions of LC3 binding proteins on mitophagy, ④ explore therapeutic methods to sensitize cervical cancer to THPN-induced autophagic cell death. Our aim is not only to clarify the regulatory mechanism of mitophagy, but also to provide theoretical basis for developing cervical cancer therapeutic drug through autophagy induction.

英文关键词： cervical cancer;nuclear receptor TR3/Nur77;autophagy;phosphorylation;signal transduction