Phase separation of Nur77 mediates XS561-induced apoptosis by promoting the formation of Nur77/Bcl-2 condensates

作     者：Xiaohui Chen Meichun Gao Yongzhen Xia Xin Wang Jingbo Qin Hongying He Weirong Liu Xiaowei Zhang Shuangzhou Peng Zhiping Zeng Ying Su Xiaokun Zhang Xiaohui Chen;Meichun Gao;Yongzhen Xia;Xin Wang;Jingbo Qin;Hongying He;Weirong Liu;Xiaowei Zhang;Shuangzhou Peng;Zhiping Zeng;Ying Su;Xiaokun Zhang

作者机构：School of Pharmaceutical ScienceFujian Provincial Key Laboratory of Innovative Drug Target ResearchXiamen UniversityXiamen 361002China NucMito Pharmaceuticals Co.Ltd.Xiamen 361000China Department of Clinical Laboratorythe Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhai 519000China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2024年第14卷第3期

页      面：1204-1221页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：partially supported by grants from the The National Natural Science Foundation of China,China(81672749 and 22207093) Xiamen Bureau of Science&Technology,Xiamen city,China(3502Z20193004 and 3502Z20150007,China) Youth Innovation Fund from Xiamen City,Fujian Province,China.(3502Z20206033) the Fujian Provincial Key Laboratory of Innovative Drug Target Research,Fujian Province,China(FJYW-2022KF01,China) 

主　　题：XS561 Nur77 Bcl-2 Apoptosis Mitochondria Phase separation TNBC TAMR 

摘      要：The orphan nuclear receptor Nur77 is a critical regulator of the survival and death of tumor *** pro-death effect of Nur77 can be regulated by its interaction with Bcl-2,resulting in conversion of Bcl-2 from a survival to *** Bcl-2 is overexpressed in various cancers preventing them from apoptosis and promoting their resistance to chemotherapy,targeting the apoptotic pathway of Nur77/Bcl-2 may lead to new cancer ***,we report our identification of XS561 as a novel Nur77 ligand that induces apoptosis of tumor cells by activating the Nur77/Bcl-2 *** vitro and animal studies revealed an apoptotic effect of XS561 in a range of tumor cell lines including MDA-MB-231 triple-negative breast cancer(TNBC)and MCF-7/LCC2 tamoxifen-resistant breast cancer(TAMR)in a Nur77-dependent *** studies showed XS561 potently induced the translocation of Nur77 from the nucleus to mitochondria,resulting in mitochondria-related ***,XS561-induced accumulation of Nur77 at mitochondria was associated with XS561 induction of Nur77 phase separation and the formation of Nur77/Bcl-2 ***,our studies identify XS561 as a new activator of the Nur77/Bcl-2 apoptotic pathway and reveal a role of phase separation in mediating the apoptotic effect of Nur77 at mitochondria.