Abstract
Omeprazole is a proton pump inhibitor that has recently been reported to exhibit anticancer activity against several types of cancer. However, the anticancer mechanisms of omeprazole remain elusive. Snail is an oncogenic zinc finger transcription factor; aberrant activation of Snail is associated with the occurrence and progression of cancer. In this study, we investigated whether Snail acted as a direct anticancer target of omeprazole. We showed that omeprazole displayed a high binding-affinity to recombinant Snail protein (Kd = 0.076 mM), suggesting that omeprazole directly and physically binds to the Snail protein. We further revealed that omeprazole disrupted CREB-binding protein (CBP)/p300-mediated Snail acetylation and then promoted Snail degradation through the ubiquitin–proteasome pathway in HCT116 cells. Omeprazole treatment markedly suppressed Snail-driven epithelial-mesenchymal transition (EMT) in aggressive HCT116, SUM159, and 4T1 cancer cells in vitro and reduced EMT-associated tumor invasion and metastasis in cancer cell xenograft models. Omeprazole also inhibited tumor growth by limiting Snail-dependent cell cycle progression. Overall, this study, for the first time, identifies Snail as a target of omeprazole and reveals a novel mechanism underlying the therapeutic effects of omeprazole against cancer. This study strongly suggests that omeprazole may be an excellent auxiliary drug for treating patients with malignant tumors.
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Acknowledgements
This research was supported by grants from the National Natural Science Foundation of China (81973363 and 82125036), the State Key Laboratory of Natural Medicines of China Pharmaceutical University (SKLNMZZCX202015), the Jiangsu Association for Science and Technology “Yong Talent Support Project”, and the Fundamental Research Funds for the Central Universities.
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ZQW and RF conceived the project, designed the experiments, and interpreted the data. YL and BXR performed the experiments, interpreted the data, and wrote the manuscript with help from HML. TL analyzed data and provided relevant advice.
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Li, Y., Ren, Bx., Li, Hm. et al. Omeprazole suppresses aggressive cancer growth and metastasis in mice through promoting Snail degradation. Acta Pharmacol Sin 43, 1816–1828 (2022). https://doi.org/10.1038/s41401-021-00787-1
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DOI: https://doi.org/10.1038/s41401-021-00787-1
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