Anticarin-β shows a promising antiosteosarcoma effect by specifically inhibiting CCT4 to impair proteostasis

查看全文 作　　者：Gan [1]Wang;Min [1,2]Zhang;Ping [1]Meng;Chengbo [1,2]Long;Xiaodong [3]Luo;Xingwei [3]Yang;Yunfei [1,4]Wang;Zhiye [1]Zhang;James [1,2,5]Mwangi;Peter Muiruri [1,2,5]Kamau;Zhi [1]Daic;Zunfu [6]Ke;Yi [7]Zhang;Wenlin [8]Chen;Xudong [1]Zhao;Fei [9]Ge;Qiumin [1,5]Lv;Mingqiang [1,5]Rong;Dongsheng [1]Li;Yang [10]Jin;Xia [11]Sheng;Ren [1,4,5,12]Lai

机构地区：[1]Key Laboratory of Animal Models and Human Disease Mechanisms,Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province,KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases,National Resource Center for Non-Human Primates,Kunming Primate Research Center,and National Research Facility for Phenotypic&Genetic Analysis of Model Animals(Primate Facility),Kunming Institute of Zoology,Kunming 650107,China;[2]University of Chinese Academy of Sciences,Beijing 100049,China;[3]State Key Laboratory of Phytochemistry and Plant Resources in West China,Kunming Institute of Botany,Chinese Academy of Sciences,Kunming 650201,China;[4]Institutes for Drug Discovery and Development,Chinese Academy of Sciences,Shanghai 201203,China;[5]Sino-African Joint Research Center,Chinese Academy of Science,Wuhan 430074,China;[6]Department of Pathology,First Afﬁliated Hospital,Sun Yat-sen University,Guangzhou 510080,China;[7]Department of Orthopaedic Surgery,First Afﬁliated Hospital of Zhengzhou University,Zhengzhou 450052,China;[8]Department of Breast Surgery,Third Afﬁliated Hospital of Kunming Medical University,Yunnan Cancer Center,Kunming 650118,China;[9]Department of Breast Surgery,First Afﬁliated Hospital of Kunming Medical University,Kunming 650032,China;[10]Department of Biosciences,University of Oslo,Oslo 0316,Norway;[11]Key Laboratory of Environment and Health,Ministry of Education&Ministry of Environmental Protection,And State Key Laboratory of Environmental Health,School of Public Health,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 434000,China;[12]Center for Biosafety Mega-Science,Chinese Academy of Sciences,Wuhan 430071,China

出　　处：《Acta Pharmaceutica Sinica B》索引2022年第12卷第5期,共12页

基　　金：the National Natural Science Foundation of China(81903666 and 31930015);the Chinese Academy of Sciences(XDB31000000,KFJ-STS-SCYD-304,and K.C.Wong Education Foundation,China);the Science and Technology Department of Yunnan Province (202101AT070301,2019ZF003,202002AA100007,202003AD150008,and 2019FB103;China);Project of Innovative Research Team of Yunnan Province(2019HC005;China);the Department of Industry and Information Technology of Yunnan Province (2019-YT-053,China)。 摘　　要：Unlike healthy, non-transformed cells, the proteostasis network of cancer cells is taxed to produce proteins involved in tumor development. Cancer cells have a higher dependency on molecular chaperones to maintain proteostasis. The chaperonin T-complex protein ring complex(TRiC) contains eight paralogous subunits(CCT1-8), and assists the folding of as many as 10% of cytosolic proteome.TRiC is essential for the progression of some cancers, but the roles of TRiC subunits in osteosarcoma remain to be explored. Here, we show that CCT4/TRiC is significantly correlated in human osteosarcoma,and plays a critical role in osteosarcoma cell survival. We identify a compound anticarin-β that can specifically bind to and inhibit CCT4. Anticarin-β shows higher selectivity in cancer cells than in normal cells. Mechanistically, anticarin-β potently impedes CCT4-mediated STAT3 maturation. Anticarin-β displays remarkable antitumor efficacy in orthotopic and patient-derived xenograft models of osteosarcoma.Collectively, our data uncover a key role of CCT4 in osteosarcoma, and propose a promising treatment strategy for osteosarcoma by disrupting CCT4 and proteostasis. 关键词：PROTEOSTASIS CCT TRiC OSTEOSARCOMA STAT3 Anticarin-β PDX model

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Anticarin-β shows a promising antiosteosarcoma effect by specifically inhibiting CCT4 to impair proteostasis

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