Omeprazole improves chemosensitivity of gastric cancer cells by m6A demethylase FTO-mediated activation of mTORC1 and DDIT3 up-regulation.
Omeprazole improves chemosensitivity of gastric cancer cells by m6A demethylase FTO-mediated activation of mTORC1 and DDIT3 up-regulation.
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DOI：
10.1042/bsr20200842
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发表时间：
2021-01-29
影响因子：
4
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Feng S;Qiu G;Yang L;Feng L;Fan X;Ren F;Huang K;Chen Y
对晚期胃癌患者的治疗效果仍不理想。质子泵抑制剂可能是一种有前景的治疗策略，可以进一步提高胃癌细胞对抗肿瘤药物的敏感性；然而，潜在的分子机制仍有待进一步阐明。本研究发现奥美拉唑预处理可增强5-Fu、DDP和TAX对胃癌细胞的抑制作用。有趣的是，由于FTO的降低，奥美拉唑预处理提高了细胞的总m6A水平。TCGA分析显示，FTO在GC组织中表达上调，与GC患者的无病生存率呈负相关。同时发现奥美拉唑诱导的FTO抑制可增强mTORC1信号通路的激活，从而抑制促生存自噬，从而提高化疗药物对胃癌细胞的抗肿瘤效果。同时，mTORC1下游的凋亡相关抑癌基因DDIT3的转录水平受奥美拉唑诱导的FTO沉默通过m6a依赖机制调控。本研究首次发现m6A修饰及其擦除剂FTO可能在质子泵抑制剂奥美拉唑介导的化疗敏感性改善中发挥作用。
The curative effect for patients with advanced gastric cancer is still unsatisfactory. Proton pump inhibitors could be a promising treatment strategy that could sensitize gastric cancer cells to antitumor drugs further; however, the underlying molecular mechanism remains to be further elucidated. In this research, it was found that omeprazole pretreatment could enhance the inhibitory effect of 5-Fu, DDP and TAX on gastric cancer cells. Interestingly, omeprazole pretreatment enhanced the total m6A level of cells due to the decreased FTO. TCGA analysis showed that FTO expression is up-regulated in GC tissues and is negatively correlated with disease-free survival of GC patients. It was also found that FTO inhibition induced by omeprazole enhanced the activation of mTORC1 signal pathway that inhibited the prosurvival autophagy so as to improve the antitumor efficiency of chemotherapeutic drugs on GC cells. Meanwhile, transcript level of DDIT3, which is an apoptosis-related tumor suppressor gene downstream of mTORC1, was regulated by omeprazole-induced FTO silence through an m6A-dependent mechanism. The present study, for the first time, found that m6A modification and its eraser FTO may play a role in the improvement of chemosensitivity mediated by proton pump inhibitor omeprazole.