2. Academic Validation
  3. Redox-sensitive cyclophilin A elicits chemoresistance through realigning cellular oxidative status in colorectal cancer

Redox-sensitive cyclophilin A elicits chemoresistance through realigning cellular oxidative status in colorectal cancer

  • Cell Rep. 2021 Nov 30;37(9):110069. doi: 10.1016/j.celrep.2021.110069.
Liyuan Peng 1,  Jingwen Jiang 1,  Hai-Ning Chen 2,  Li Zhou 1,  Zhao Huang 1,  Siyuan Qin 1,  Ping Jin 1,  Maochao Luo 1,  Bowen Li 1,  Jiayan Shi 1,  Na Xie 3,  Lih-Wen Deng 4,  Yih-Cherng Liou 5,  Edouard C Nice 6,  Canhua Huang 7,  Yuquan Wei 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu 610041, P.R. China; West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, P.R. China.
  • 2 Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P.R. China.
  • 3 West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, P.R. China.
  • 4 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore.
  • 5 Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 117543, Singapore; Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 117573, Singapore.
  • 6 Department of Biochemistry and Molecular Biology, Monash University, Clayton VIC 3800, Australia.
  • 7 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu 610041, P.R. China; West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, P.R. China. Electronic address: hcanhua@hotmail.com.
  • 8 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu 610041, P.R. China.
PMID: 34852234 DOI: 10.1016/j.celrep.2021.110069
Abstract

Cancer cells utilize rapidly elevated cellular antioxidant programs to accommodate chemotherapy-induced oxidative stress; however, the underlying mechanism remains largely unexplored. Here we screen redox-sensitive effectors as potential therapeutic targets for colorectal Cancer (CRC) treatment and find that Cyclophilin A (CypA) is a compelling candidate. Our results show that CypA forms an intramolecular disulfide bond between Cys115 and Cys161 upon oxidative stress and the oxidized cysteines in CypA are recycled to a reduced state by peroxiredoxin-2 (PRDX2). Furthermore, CypA reduces cellular Reactive Oxygen Species levels and increases CRC cell survival under insults of H2O2 and chemotherapeutics through a CypA-PRDX2-mediated antioxidant apparatus. Notably, CypA is upregulated in chemoresistant CRC samples, which predicts poor prognosis. Moreover, targeting CypA by cyclosporine A exhibits promising efficacy against chemoresistant CRC when combined with chemotherapeutics. Collectively, our findings highlight CypA as a component of cellular noncanonical antioxidant defense and as a potential druggable therapeutic target to ameliorate CRC chemoresistance.

Keywords

CRC; CypA; PRDX2; ROS; antioxidant system; colorectal cancer; disulfide bond; drug resistance; oxidative stress; reactive oxygen species; redox modification; redox signaling.

Figures
Products