4.7 Article

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

期刊

ACTA PHARMACEUTICA SINICA B
卷 12, 期 5, 页码 2268-2279

出版社

INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2021.12.024

关键词

Proteostasis; CCT; TRiC; Osteosarcoma; STAT3; Anticarin-beta; PDX model

资金

  1. National Natural Science Foundation of China [81903666, 31930015]
  2. Chinese Academy of Sciences [XDB31000000, KFJ-STS-SCYD-304]
  3. K. C. Wong Education Foundation
  4. China
  5. Science and Technology Department of Yunnan Province (China) [202101AT070301, 2019ZF003, 202002AA100007, 202003AD150008, 2019FB103]
  6. Project of Innovative Research Team of Yunnan Province (China) [2019HC005]
  7. Department of Industry and Infor-mation Technology of Yunnan Province (China) [2019-YT-053]

向作者/读者索取更多资源

Unlike healthy cells, cancer cells heavily rely on the molecular chaperone protein TRiC, particularly its subunit CCT4, for protein folding and maintenance of proteostasis. In this study, we demonstrate that targeting CCT4 with the compound anticarin-beta can effectively inhibit osteosarcoma cell survival and impede STAT3 maturation. Anticarin-beta shows high selectivity for cancer cells and exhibits remarkable antitumor efficacy in orthotopic and patient-derived xenograft models of osteosarcoma.
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-beta that can specifically bind to and inhibit CCT4. Anticarin-beta shows higher selectivity in cancer cells than in normal cells. Mechanistically, anticarin-beta potently impedes CCT4-mediated STAT3 maturation. Anticarin-beta 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. (C) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

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