| 作者: |
Wang, Gan; Zhang, Min; Meng, Ping; Long, Chengbo; Luo, Xiaodong; Yang, Xingwei; Wang, Yunfei; Zhang, Zhiye; Mwangi, James; Kamau, Peter Muiruri; Dai, Zhi; Ke, Zunfu; Zhang, Yi; Chen, Wenlin; Zhao, Xudong; Ge, Fei; Lv, Qiumin; Rong, Mingqiang; Li, Dongsheng; Jin, Yang; Sheng, Xia; Lai, Ren |
| 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-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 |
