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• W3082676535 abstract "Background: Oxidative stress from elevated reactive oxygen species (ROS) has been reported to induce cell apoptosis and may provide a means to target cancer cells. Celastrol is a natural bioactive compound that was recently shown to increase ROS levels and cause apoptosis in cancer cells. However, the underlying mechanism for this cytotoxic action remains unclear and direct molecular targets of Celastrol have not been identified. Methods: Proteome microarray, surface plasmon resonance, isothermal titration calorimetry and molecular simulation were used to identify the molecular target of Celastrol. Binding and activity assays were used to validate the interaction of Celastrol with target protein in cell-free and gastric cancer cell lysates. We then assessed target transcript levels in in biopsy specimens obtained from patients with gastric cancer. Gastric cancer growth-limiting and cytotoxic activity of Celastrol was evaluated in BALB/c nu/nu mice. Results: Our data show that Celastrol directly binds to an antioxidant enzyme, peroxiredoxin-2 (Prdx2), which then inhibits its enzyme activity at both molecular and cellular level. Inhibition of Prdx2 by Celastrol increased cellular ROS levels and led to ROS-dependent endoplasmic reticulum stress, mitochondrial dysfunction, and apoptosis in gastric cancer cells. Functional tests demonstrated that Celastrol limits gastric cancer cells, at least in part, through targeting Prdx2. Celastrol treatment of mice implanted with gastric cancer cells also inhibited tumor growth, associated with Prdx2 inhibition and increased ROS. Analysis of human gastric cancer also showed increased Prdx2 levels and correlation with survival. Conclusion: Our studies have uncovered a potential Celastrol-interacting protein Prdx2 and a ROS-dependent mechanism of its action. The findings also highlight Prdx2 as a potential target for the treatment of gastric cancer." @default.
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• W3082676535 date "2020-01-01" @default.
• W3082676535 modified "2023-10-15" @default.
• W3082676535 title "Celastrol induces ROS-mediated apoptosis via directly targeting peroxiredoxin-2 in gastric cancer cells" @default.
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• W3082676535 doi "https://doi.org/10.7150/thno.46728" @default.
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