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

Acta Pharmaceutica Sinica B 2022年第5期12卷 2268-2279页

作者： Gan Wang Min Zhang Ping Meng Chengbo Long Xiaodong Luo Xingwei Yang Yunfei Wang zhiye Zhang James Mwangi Peter Muiruri Kamau zhi daic Zunfu Ke Yi Zhang Wenlin Chen Xudong Zhao Fei Ge Qiumin Lv Mingqiang Rong Dongsheng Li Yang Jin Xia Sheng Ren Lai Key Laboratory of Animal Models and Human Disease Mechanisms Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan ProvinceKIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesNational Resource Center for Non-Human PrimatesKunming Primate Research Centerand National Research Facility for Phenotypic&Genetic Analysis of Model Animals(Primate Facility)Kunming Institute of ZoologyKunming 650107China University of Chinese Academy of Sciences Beijing 100049China State Key Laboratory of Phytochemistry and Plant Resources in West China Kunming Institute of BotanyChinese Academy of SciencesKunming 650201China Institutes for Drug Discovery and Development Chinese Academy of SciencesShanghai 201203China Sino-African Joint Research Center Chinese Academy of ScienceWuhan 430074China Department of Pathology First Afﬁliated HospitalSun Yat-sen UniversityGuangzhou 510080China Department of Orthopaedic Surgery First Afﬁliated Hospital of Zhengzhou UniversityZhengzhou 450052China Department of Breast Surgery Third Afﬁliated Hospital of Kunming Medical UniversityYunnan Cancer CenterKunming 650118China Department of Breast Surgery First Afﬁliated Hospital of Kunming Medical UniversityKunming 650032China Department of Biosciences University of OsloOslo 0316Norway Key Laboratory of Environment and Health Ministry of Education&Ministry of Environmental ProtectionAnd State Key Laboratory of Environmental HealthSchool of Public HealthTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 434000China Center for Biosafety Mega-Science Chinese Academy of SciencesWuhan 430071China

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 *** 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 ***, 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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