Omeprazole improves chemosensitivity of gastric cancer cells by m6A demethylase FTO-mediated activation of mTORC1 and DDIT3 up-regulation

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...

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Bibliographic Details
Published in:Bioscience reports 2021-01, Vol.41 (1)
Main Authors: Feng, Shuitu, Qiu, Guoqin, Yang, Lihong, Feng, Lihua, Fan, Xin, Ren, Fang, Huang, Kaida, Chen, Yide
Format: Article
Language:English
Subjects:
Antibodies
Antineoplastic drugs
Apoptosis
Autophagy
Biotechnology
Cancer
Cancer therapies
Cell Cycle, Growth & Proliferation
Chemotherapy
Drug interactions
Drugs
Efficiency
Experiments
Gastric cancer
Gene Expression & Regulation
Genes
Medical prognosis
Molecular Interactions
Molecular modelling
N6-methyladenosine
Omeprazole
Pretreatment
Proton pump inhibitors
Protons
Tumor suppressor genes
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Summary: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.
ISSN:0144-8463
1573-4935
DOI:10.1042/bsr20200842