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Aberrant human ClpP activation disturbs mitochondrial proteome homeostasis to suppress pancreatic ductal adenocarcinoma

文献类型：期刊论文

作者Wang, Pengyu8,9; Zhang, Tao9; Wang, Xinjing7; Xiao, Hongying5,6; Li, Huiti4; Shou, Lin-Lin8,9; Yang, Teng3,9; Wei, Bingyan2,8,9; Zhu, Zeyun4; Zhou, Lu4
刊名CELL CHEMICAL BIOLOGY
出版日期2022-09-15
卷号29期号:9页码:1396-+
ISSN号2451-9456
DOI10.1016/j.chembiol.2022.07.002
通讯作者Yang, Cai-Guang(yangcg@simm.ac.cn)
英文摘要The mitochondrial caseinolytic protease P (ClpP) is a target candidate for treating leukemia; however, the ef-fects of ClpP modulation on solid tumors have not been adequately explored. Here, we report a potent acti-vator of ClpP with the therapeutic potential for pancreatic ductal adenocarcinoma (PDAC). We first validated that aberrant ClpP activation leads to growth arrest of PDAC cells and tumors. We then performed high -throughput screening and synthetic optimization, from which we identified ZG111, a potent activator of ClpP. ZG111 binds to ClpP and promotes the ClpP-mediated degradation of respiratory chain complexes. This degradation activates the JNK/c-Jun pathway, induces the endoplasmic reticulum stress response, and consequently causes the growth arrest of PDAC cells. ZG111 also produces inhibitory effects on tumor growth in cell line-derived and patient-derived xenograft mouse models. Altogether, our data demonstrate a promising therapeutic strategy for PDAC suppression through the chemical activation of ClpP.
WOS关键词ANTICANCER COMPOUNDS ; MOLECULE INHIBITOR ; PROTEASE ; METABOLISM ; CRYSTALLOGRAPHY ; DYSREGULATION ; IMIPRIDONES ; ICG-001 ; SYSTEM ; TARGET
资助项目National Nat- ural Science Foundation of China[22037007] ; National Nat- ural Science Foundation of China[21725801] ; National Nat- ural Science Foundation of China[22107109]
WOS研究方向Biochemistry & Molecular Biology
语种英语
出版者CELL PRESS
WOS记录号WOS:000874938100005
源URL[http://119.78.100.183/handle/2S10ELR8/303106]  
专题新药研究国家重点实验室
通讯作者Yang, Cai-Guang
作者单位1.Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China
2.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
3.Guizhou Univ, Ctr R&D Fine Chem, State Key Lab Breeding Base Green Pesticide & Agr, Key Lab Green Pesticide & Agr Bioengn,Minist Educ, Guiyang 550025, Peoples R China
4.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China
5.Tsinghua Univ, Sch Life Sci, Joint Grad Program Peking Tsinghua NIBS, Beijing 100084, Peoples R China
6.Tsinghua Univ, Tsinghua Peking Ctr Life Sci, Sch Pharmaceut Sci, MOE Key Lab Bioorgan Phosphorus Chem & Chem Biol, Beijing 100084, Peoples R China
7.Shanghai Jiao Tong Univ, Ruijin Hosp, Res Inst Pancreat Dis, Shanghai Inst Digest Surg, Shanghai 200025, Peoples R China
8.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
9.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Chem Biol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Pengyu,Zhang, Tao,Wang, Xinjing,et al. Aberrant human ClpP activation disturbs mitochondrial proteome homeostasis to suppress pancreatic ductal adenocarcinoma[J]. CELL CHEMICAL BIOLOGY,2022,29(9):1396-+.
APA Wang, Pengyu.,Zhang, Tao.,Wang, Xinjing.,Xiao, Hongying.,Li, Huiti.,...&Yang, Cai-Guang.(2022).Aberrant human ClpP activation disturbs mitochondrial proteome homeostasis to suppress pancreatic ductal adenocarcinoma.CELL CHEMICAL BIOLOGY,29(9),1396-+.
MLA Wang, Pengyu,et al."Aberrant human ClpP activation disturbs mitochondrial proteome homeostasis to suppress pancreatic ductal adenocarcinoma".CELL CHEMICAL BIOLOGY 29.9(2022):1396-+.

入库方式： OAI收割

来源：上海药物研究所

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