Proton Pump Inhibitors Induce Cell Cycle Arrest and Enhance Chemosensitivity of Gastric Cancer Cells by Inhibiting Cell Cycle-related Genes
10.3969/j.issn.1008-7125.2021.09.002
- Author:
Meng SU
1
;
Bin ZHANG
1
;
Lei WANG
1
;
Guifang XU
1
;
Ying LÜ
1
;
Xiaoping ZOU
1
;
Min CHEN
2
Author Information
1. Department of Gastroenterology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University
2. Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School
- Publication Type:Journal Article
- Keywords:
Cell Cycle;
Chemosensitivity;
G2/M Arrest;
Proton Pump Inhibitors;
Stomach Neoplasms
- From:Chinese Journal of Gastroenterology
2021;26(9):519-525
- CountryChina
- Language:Chinese
-
Abstract:
Background: Several studies have shown that proton pump inhibitors (PPIs) can enhance the sensitivity of gastric cancer (GC) cells to chemotherapy and inhibit tumor proliferation and invasion. Aims: To investigate whether PPI could enhance chemosensitivity by inhibition of cell cycle-related genes in GC cells. Methods: Two human GC cell lines, AGS and HGC27 were treated with pantoprazole in different concentrations, and the cell viability was detected by CCK-8 assay. Transcriptome sequencing combined with KEGG enrichment analysis were used to determine the effect of PPI on cell cycle of GC cells, and the changes of cell cycle and its related genes were validated by flow cytometry, real-time PCR and Western blotting, respectively. Bioinformatics websites were employed to analyze the major differentially expressed cell cycle-related genes in GCs and their relationship with patients' prognosis. After transfection with FOXM1 plasmid or control plasmid, the inhibitory effect of PPI combined with cisplatin on GC cells was determined by CCK-8 assay. Results: PPI inhibited the proliferation of GC cells effectively in vitro. Transcriptome sequencing showed that the expression levels of G2/M phase-related genes, including FOXM1, PLK1, and AURKB were down-regulated in PPI-treated GC cells, and G2/M arrest was suggested by KEGG enrichment analysis. All these changes were proved by flow cytometry, real-time PCR and Western blotting. Bioinformatics analysis revealed that FOXM1, PLK1, and AURKB genes were highly expressed in GCs and correlated with a poor prognosis. The inhibitory effect of PPI combined with cisplatin on GC cells was superior to that of cisplatin alone, but could be partially reversed by overexpression of FOXM1. Conclusions: PPI treatment can induce G2/M arrest in GC cells by inhibiting cell cycle-related genes, and subsequently enhance the sensitivity of GC cells to chemotherapy.
