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Molecular mechanism by which RRM2-inhibitor (cholagogue osalmid) plus bafilomycin A1 cause autophagic cell death in multiple myeloma

文献类型：期刊论文

作者Guo, Shushan3; Xu, Zhijian2; Feng, Qilin3; Zhang, Hui3; Yu, Dandan1; Li, Bo2; Fu, Ke3; Gao, Xuejie3; Zhang, Qikai3; Yi, Hongfei1
刊名ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
出版日期2023-10-01
卷号747页码:12
关键词Autophagy RRM2 p62 RIPK3 Cholagogue osalmid Bafilomycin A1
ISSN号0003-9861
DOI10.1016/j.abb.2023.109771
通讯作者Zhu, Weiliang(wlzhu@simm.ac.cn) ; Shi, Jumei(shijumei@tongji.edu.cn)
英文摘要Despite significant improvement in the prognosis of multiple myeloma (MM), the disease remains incurable; thus, more effective therapies are required. Ribonucleoside-diphosphate reductase subunit M2 (RRM2) is significantly associated with drug resistance, rapid relapse, and poor prognosis. Previously, we found that 4-hydroxysalicylanilide (osalmid), a specific inhibitor of RRM2, exhibits anti-MM activity in vitro, in vivo, and in human patients; however, the mechanism remains unclear. Osalmid inhibits the translocation of RRM2 to the nucleus and stimulates autophagosome synthesis but inhibits subsequent autophagosome-lysosome fusion. We confirm that RRM2 binds to receptor-interacting protein kinase 3 (RIPK3) and reduces RIPK3, inhibiting auto-phagosome-lysosome fusion. Interestingly, the combination of osalmid and bafilomycin A1 (an autophagy in-hibitor) depletes RIPK3 and aggravates p62 and autophagosome accumulation, leading to autophagic cell death. Combination therapy demonstrates synergistic cytotoxicity both in vitro and in vivo. Therefore, we propose that combining osalmid and bafilomycin A1(BafA1) may have clinical benefits against MM.
资助项目National Natural Science Founda-tion of China[82070224] ; National Natural Science Founda-tion of China[81971529] ; National Natural Science Founda-tion of China[82170190] ; National Natural Science Founda-tion of China[82170201] ; National Natural Science Founda-tion of China[82170200]
WOS研究方向Biochemistry & Molecular Biology ; Biophysics
语种英语
WOS记录号WOS:001095886100001
出版者ELSEVIER SCIENCE INC
源URL[http://119.78.100.183/handle/2S10ELR8/307727]  
专题新药研究国家重点实验室
通讯作者Zhu, Weiliang; Shi, Jumei
作者单位1.Tongji Univ, Shanghai Peoples Hosp 10, Sch Med, Dept Hematol, Shanghai 200072, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Tongji Univ, Shanghai East Hosp, Sch Med, Dept Hematol, Shanghai 200120, Peoples R China
推荐引用方式
GB/T 7714		 Guo, Shushan,Xu, Zhijian,Feng, Qilin,et al. Molecular mechanism by which RRM2-inhibitor (cholagogue osalmid) plus bafilomycin A1 cause autophagic cell death in multiple myeloma[J]. ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS,2023,747:12.
APA Guo, Shushan.,Xu, Zhijian.,Feng, Qilin.,Zhang, Hui.,Yu, Dandan.,...&Shi, Jumei.(2023).Molecular mechanism by which RRM2-inhibitor (cholagogue osalmid) plus bafilomycin A1 cause autophagic cell death in multiple myeloma.ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS,747,12.
MLA Guo, Shushan,et al."Molecular mechanism by which RRM2-inhibitor (cholagogue osalmid) plus bafilomycin A1 cause autophagic cell death in multiple myeloma".ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 747(2023):12.

入库方式： OAI收割

来源：上海药物研究所

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