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Anticarin-β shows a promising anti-osteosarcoma effect by specifically inhibiting CCT4 to impair proteostasis
Gan Wang1, Min Zhang1,2, Ping Meng1
1Key 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.
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.
Insights
Cancer cells rely on the T-complex protein ring complex (TRiC) for survival. A new compound, anticarin-β, targets the CCT4 subunit of TRiC, showing promise for osteosarcoma treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cancer cells exhibit increased proteostasis demands, creating a dependency on molecular chaperones.
- The T-complex protein ring complex (TRiC) is crucial for folding approximately 10% of the cytosolic proteome and is implicated in cancer progression.
- The specific roles of TRiC subunits in osteosarcoma pathogenesis are not well understood.
Purpose of the Study:
- To investigate the role of TRiC subunits in osteosarcoma.
- To identify and characterize novel therapeutic strategies targeting TRiC in osteosarcoma.
Main Methods:
- Correlation analysis of CCT4 expression in human osteosarcoma tissues.
- In vitro and in vivo studies using anticarin-β, a novel CCT4 inhibitor.
- Assessment of CCT4-mediated STAT3 maturation and antitumor efficacy in osteosarcoma models.
Main Results:
- CCT4 expression is significantly correlated with human osteosarcoma.
- Anticarin-β selectively inhibits CCT4 in cancer cells, impeding STAT3 maturation.
- Anticarin-β demonstrated significant antitumor efficacy in both orthotopic and patient-derived xenograft osteosarcoma models.
Conclusions:
- CCT4 plays a critical role in osteosarcoma cell survival and progression.
- Targeting CCT4 with anticarin-β represents a promising therapeutic strategy for osteosarcoma by disrupting cancer cell proteostasis.
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