Nur77孤儿核受体药物靶点的乙酰化、泛素化、亚细胞定位及其介导的抗癌新机制的研究

Nur77是一种孤儿核受体，是近年来引起广泛关注的一个潜在的药物靶点。Nur77的抗癌作用主要与其出核转位有关，但有关调控机制仍不清楚。本项目的前期研究发现，Nur77的一些小分子调控剂如厚朴酚衍生物，可调控Nur77乙酰化和泛素化水平，引导其在内质网和线粒体之间转位。本项目将基于前期的新发现，系统研究Nur77在肝癌细胞中介导厚朴酚衍生物的抗癌作用，重点围绕这类化合物如何通过诱导Nur77与Sirt3、Trim13的相互作用，调控Nur77的不同修饰、可能的切割、转位，及其介导的内质网应激、自噬、线粒体凋亡的交互作用和网络，揭示Nur77介导的抗癌新机制，为发展以Nur77为靶点的新型抗癌药物奠定理论基础。

Nur77, an orphan nuclear receptor, is emerging as a potential and promising drug target, which has attracted great attention in recent years. The anticancer activity of Nur77 is mainly attributed to its nuclear export, however, the underlying mechanism remains largely unknown. In our pilot study, we found that magnolol derivatives could regulate Nur77 acetylation and ubiquitination levels, which in turn directed Nur77 translocation between endoplasmic reticulum (ER) and mitochondria. Based on these preliminary findings, this study will explore Nur77-mediated anticancer activity of honokiol derivatives. Especially, we will focus on the interaction of Nur77 with Sirt3 and Trim13, exploring the role of Sirt3 and Trim13 in regulating Nur77 modification, cleavage and translocation, as well as Nur77-dependent cross-talk and network of ER stress, autophagy and mitochondrial apoptosis induced by magnolol derivatives. Dissecting the novel mechanism of Nur77-mediated anticancer activity will provide a theoretical basis for developing new Nur77-targeted anticancer drugs.