Investigation of targets and anticancer mechanisms of covalently acting natural products by functional proteomics  

作　　者：Wen-si Zhao Kai-feng Chen Man Liu Xing-long Jia Yu-qi Huang Bing-bing Hao Hao Hu Xiao-yan Shen Qiang Yu Min-jia Tan 

机构地区：[1]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China [2]University of Chinese Academy of Sciences,Beijing,101408,China [3]Zhongshan Institute for Drug Discovery,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Zhongshan,528400,China [4]Department of Pharmacology,School of Pharmacy,Fudan University,Shanghai,201203,China [5]Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening,College of Pharmacy,Jiangsu Ocean University,Lianyungang,222005,China

出　　处：《Acta Pharmacologica Sinica》2023年第8期1701-1711,共11页中国药理学报（英文版）

基　　金：supported by the National Key R&D Program of China (2020YFE0202200);the National Natural Science Foundation of China (32071432,21907100,22225702);the Program of Shanghai Academic Research Leader (22XD1420900);the Science and Technology Commission of Shanghai Municipality (19JC1416300);the Natural Science Foundation of China for Innovation Research Group (81821005);the Shanghai Sailing Program (21YF1456000);the open fund of state key laboratory of Pharmaceutical Biotechnology,Nanjing University,China (KF-202201);the National Key R&D Program of China (2018YFC1705500).

摘　　要：Eriocalyxin B(EB),17-hydroxy-jolkinolide B(HJB),parthenolide(PN),xanthatin(XT)and andrographolide(AG)are terpenoid natural products with a variety of promising antitumor activities,which commonly bear electrophilic groups(α,β–unsaturated carbonyl groups and/or epoxides)capable of covalently modifying protein cysteine residues.However,their direct targets and underlying molecular mechanisms are still largely unclear,which limits the development of these compounds.In this study,we integrated activity-based protein profiling(ABPP)and quantitative proteomics approach to systematically characterize the covalent targets of these natural products and their involved cellular pathways.We first demonstrated the anti-proliferation activities of these five compounds in triple-negative breast cancer cell MDA-MB-231.Tandem mass tag(TMT)-based quantitative proteomics showed all five compounds commonly affected the ubiquitin mediated proteolysis pathways.ABPP platform identified the preferentially modified targets of EB and PN,two natural products with high anti-proliferation activity.Biochemical experiments showed that PN inhibited the cell proliferation through targeting ubiquitin carboxyl-terminal hydrolase 10(USP10).Together,this study uncovered the covalently modified targets of these natural products and potential molecular mechanisms of their antitumor activities.

关 键 词：natural products PROTEOMICS ABPP eriocalyxin B PARTHENOLIDE 

分 类 号：R589.2[医药卫生—内分泌]