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

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

扫码查看
原文链接
  • NETL
  • NSTL
  • 万方数据
The orphan nuclear receptor Nur77 is a critical regulator of the survival and death of tumor cells.The pro-death effect of Nur77 can be regulated by its interaction with Bcl-2,resulting in conversion of Bcl-2 from a survival to killer.As 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 therapeutics.Here,we report our identification of XS561 as a novel Nur77 ligand that induces apoptosis of tumor cells by activating the Nur77/Bcl-2 pathway.In 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 manner.Mechanistic studies showed XS561 potently induced the trans-location of Nur77 from the nucleus to mitochondria,resulting in mitochondria-related apoptosis.Interest-ingly,XS561-induced accumulation of Nur77 at mitochondria was associated with XS561 induction of Nur77 phase separation and the formation of Nur77/Bcl-2 condensates.Together,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.

XS561Nur77Bcl-2ApoptosisMitochondriaPhase separationTNBCTAMR

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

展开 >

School of Pharmaceutical Science,Fujian Provincial Key Laboratory of Innovative Drug Target Research,Xiamen University,Xiamen 361002,China

Department of Clinical Laboratory,the Fifth Affiliated Hospital of Sun Yat-sen University,Zhuhai 519000,China

NucMito Pharmaceuticals Co.,Ltd.,Xiamen 361000,China

The National Natural Science Foundation of China,ChinaThe National Natural Science Foundation of China,ChinaXiamen Bureau of Science and Technology,Xiamen city,ChinaXiamen Bureau of Science and Technology,Xiamen city,ChinaYouth Innovation Fund from Xiamen City,Fujian Province,ChinaFujian Provincial Key Laboratory of Innovative Drug Target Research,Fujian Province,China

81672749222070933502Z201930043502Z201500073502Z20206033FJ-YW-2022KF01

2024

10.1016/j.apsb.2023.11.017

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(3)
  • 58