Omeprazole suppresses aggressive cancer growth and metastasis in mice through promoting Snail degradation
Omeprazole suppresses aggressive cancer growth and metastasis in mice through promoting Snail degradation
复制标题
DOI：
10.1038/s41401-021-00787-1
复制
发表时间：
2021-11-16
影响因子：
8.2
通讯作者：
Wu, Zhao-qiu
中科院分区：
文献类型：
--
作者：
Li, Yang;Ren, Bo-xue;Wu, Zhao-qiu
奥美拉唑是一种质子泵抑制剂，最近有报道显示它对几种类型的癌症具有抗癌活性。然而，奥美拉唑的抗癌机制仍然不清楚。Snail是一种致癌的锌指转录因子；Snail的异常激活与癌症的发生和发展有关。在这项研究中，我们研究了Snail是否作为奥美拉唑的直接抗癌靶点。结果表明，奥美拉唑与重组蜗牛蛋白具有较高的结合亲和力(K-d=0.076 mM)，表明奥美拉唑与重组蜗牛蛋白直接和物理结合。我们进一步揭示了奥美拉唑阻断了CREB结合蛋白(CBP)/p300介导的Snail乙酰化，进而通过泛素-蛋白酶体途径促进了Snail的降解。奥美拉唑治疗显著抑制体外侵袭性HCT116、SUM159和4T1癌细胞的蜗牛驱动的上皮-间充质转化(EMT)，并减少EMT相关的肿瘤侵袭和转移。奥美拉唑还通过限制蜗牛依赖的细胞周期进程来抑制肿瘤生长。总体而言，这项研究首次将Snail确定为奥美拉唑的靶标，并揭示了奥美拉唑抗癌疗效的新机制。本研究有力地提示奥美拉唑可能是治疗恶性肿瘤患者的一种很好的辅助药物。
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 (K-d = 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.