Abstract
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.
Highlights
Gastric cancer (GC) is one of the most common cancers all over the word that is currently the second-leading cause of cancer related death among both men and women in China [1]
The conclusion that proton pump inhibitor (PPI) could function as a promising treatment strategy for gastric cancer due to their significantly sensitize gastric cancer cells to antitumor drugs has been made by our research group and others [4,5,6]
The results showed that three antitumor drugs can significantly reduce the relative survival rate of AGS and HGC-27 cells
Summary
Gastric cancer (GC) is one of the most common cancers all over the word that is currently the second-leading cause of cancer related death among both men and women in China [1]. Significant improvements including surgery, radiation therapy, chemotherapy, targeted therapy or immunotherapy alone or in combination have been made in the treatment measures for gastric cancer [2]. A better understanding of the factors and potential molecular mechanism involved in improving the response efficiency of GC cells to therapeutic methods has very important clinical significance. The conclusion that PPIs could function as a promising treatment strategy for gastric cancer due to their significantly sensitize gastric cancer cells to antitumor drugs has been made by our research group and others [4,5,6]. It was found that PPIs directly inhibited cancer cell proliferation, drug resistance-induced metastasis and regulate stemness of GC cancer cells [5,7,8]
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