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

Abstract

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.

• Authors: Gan Wang, Min Zhang, Ping Meng, Chengbo Long, Xiaodong Luo, Xingwei Yang, Yunfei Wang, Zhiye Zhang, James Mwangi, Peter Muiruri Kamau, Zhi Dai, Zunfu Ke, Yi Zhang, Wenlin Chen, Xudong Zhao, Fei Ge, Qiumin Lv, Mingqiang Rong, Dongsheng Li, Yang Jin, Xia Sheng, Ren Lai
• Journal: Acta pharmaceutica Sinica. B (Acta Pharm Sin B) Vol. 12 Issue 5 Pg. 2268-2279 (May 2022) ISSN: 2211-3835 [Print] Netherlands
• PMID: 35646538 (Publication Type: Journal Article)
• Copyright: © 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.