AI Article Synopsis
- Cancer cells respond to chemotherapy-induced oxidative stress by enhancing their antioxidant defenses, and this study investigates the role of cyclophilin A (CypA) as a potential target in colorectal cancer (CRC) therapy.
- CypA plays a key role in countering oxidative stress by forming a disulfide bond under stress conditions and working with peroxiredoxin-2 (PRDX2) to recycle oxidized cysteines, thereby lowering reactive oxygen species levels and promoting cell survival.
- Increased levels of CypA in chemoresistant CRC indicate a poor prognosis, and targeting CypA with the drug cyclosporine A shows promise in enhancing the effectiveness of chemotherapy for resistant cases of CRC
Article 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 HO 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.
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| http://dx.doi.org/10.1016/j.celrep.2021.110069 | DOI Listing |
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