Anticarin-β shows a promising anti-osteosarcoma effect by specifically inhibiting CCT4 to impair proteostasis.
10.1016/j.apsb.2021.12.024
- Author:
Gan WANG
1
;
Min ZHANG
1
;
Ping MENG
1
;
Chengbo LONG
1
;
Xiaodong LUO
2
;
Xingwei YANG
2
;
Yunfei WANG
1
;
Zhiye ZHANG
1
;
James MWANGI
1
;
Peter Muiruri KAMAU
1
;
Zhi DAI
2
;
Zunfu KE
3
;
Yi ZHANG
4
;
Wenlin CHEN
5
;
Xudong ZHAO
1
;
Fei GE
6
;
Qiumin LV
1
;
Mingqiang RONG
1
;
Dongsheng LI
1
;
Yang JIN
7
;
Xia SHENG
8
;
Ren LAI
1
Author Information
1. Key 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.
2. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
3. Department of Pathology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
4. Department of Orthopaedic Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
5. Department of Breast Surgery, Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Center, Kunming 650118, China.
6. Department of Breast Surgery, First Affiliated Hospital of Kunming Medical University, Kunming 650032, China.
7. Department of Biosciences, University of Oslo, Oslo 0316, Norway.
8. Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, And State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 434000, China.
- Publication Type:Journal Article
- Keywords:
Anticarin-β;
CCT;
Osteosarcoma;
PDX model;
Proteostasis;
STAT3;
TRiC
- From:
Acta Pharmaceutica Sinica B
2022;12(5):2268-2279
- CountryChina
- Language:English
-
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.
