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

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.

• Authors: Liyuan Peng, Jingwen Jiang, Hai-Ning Chen, Li Zhou, Zhao Huang, Siyuan Qin, Ping Jin, Maochao Luo, Bowen Li, Jiayan Shi, Na Xie, Lih-Wen Deng, Yih-Cherng Liou, Edouard C Nice, Canhua Huang, Yuquan Wei
• Journal: Cell reports (Cell Rep) Vol. 37 Issue 9 Pg. 110069 (11 30 2021) ISSN: 2211-1247 [Electronic] United States
• PMID: 34852234 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Antioxidants
• Reactive Oxygen Species
• Oxaliplatin
• PRDX2 protein, human
• Peroxiredoxins
• Cyclophilin A
• Fluorouracil

Topics

• Adult
• Aged
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Antioxidants (pharmacology)
• Apoptosis
• Cell Proliferation
• Colorectal Neoplasms (drug therapy, metabolism, pathology)
• Cyclophilin A (genetics, metabolism)
• Drug Resistance, Neoplasm
• Female
• Fluorouracil (administration & dosage)
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Oxaliplatin (administration & dosage)
• Oxidation-Reduction
• Oxidative Stress
• Peroxiredoxins (genetics, metabolism)
• Prognosis
• Reactive Oxygen Species
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays