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.