Abstract
Intracellular proton extrusion in gastric cancer cells has been reported to promote cancer cell survival under acidic conditions via hydrogen/potassium adenosine triphosphatase (H+/K+-ATPase). Rabeprazole is a frequently used second-generation proton pump inhibitor (PPI) that irreversibly inactivates gastric H+/K+-ATPase. Therefore, we hypothesized that rabeprazole could reduce the viability of gastric cancer cells. In the present study, four human gastric cancer cell lines and one non-cancer gastric cell line were cultured. Cell viability, the α- and β-subunits of H+/K+-ATPase and cellular apoptosis were analyzed by dye exclusion assay, reverse transcription-polymerase chain reaction and annexin V-fluorescein isothiocyanate/propidium iodide staining, respectively. The expression level of total extracellular signal-regulated protein kinase 1/2 (ERK 1/2) and phosphorylated-ERK protein was detected by western blot analysis. Gastric cancer cell lines were more tolerant of the acidic culture media than non-cancer cells. Administration of rabeprazole led to a marked decrease in the viability of MKN-28 cells. Exposure to rabeprazole induced significant apoptosis in AGS cells. Rabeprazole completely inhibited the phosphorylation of ERK 1/2 in the MKN-28 cells, whereas the same effect was not observed in either the KATO III or MKN-45 cells. The ERK 1/2 inhibitor, PD98059, attenuated the viability of the AGS cells. A similar antiproliferative effect was observed in the rabeprazole treatment group. In addition, PD98059 and rabeprazole were able to efficaciously inhibit the phosphorylation of ERK 1/2 in the gastric cancer cells. Therefore, it was concluded that rabeprazole can attenuate the cell viability of human gastric cancer cells through inactivation of the ERK1/2 signaling pathway. The results of the present study demonstrate that rabeprazole inhibits the viability of gastric cancer cells in vitro and may serve as a novel antineoplastic agent.
Highlights
Hydrogen/potassium adenosine triphosphatase (H+/K+‐ATPase), normally contained within the lumen of gastric parietal cells, plays a vital role in the maintenance of cellular pH homeostasis by exchanging luminal K+ for cytoplasmic H+
The gastric cancer cells were highly tolerant of acidic culture media compared with the non‐cancer cells, whose viability significantly decreased at a lower pH value of pH 5.5
The MKN‐28 cells displayed significant attenuation in cell viability compared with the KATO III and MKN‐45 cells following rabeprazole treatment (Fig. 2A). These results indicated that the sensitivity to rabeprazole‐induced apoptosis in gastric cancer cells may be correlated with the inhibitory efficacy of rabeprazole on extracellular signal‐regulated protein kinase 1/2 (ERK 1/2) phosphorylation
Summary
Hydrogen/potassium adenosine triphosphatase (H+/K+‐ATPase), normally contained within the lumen of gastric parietal cells, plays a vital role in the maintenance of cellular pH homeostasis by exchanging luminal K+ for cytoplasmic H+. This particular proton pump participates in the formation of the abnormal pH gradients that are typical of gastric cancer cells during tumorigenesis [1]. PPIs are prodrugs that require protonation in acidic conditions for full activation [4] In their acid‐activated form, PPIs bind covalently through disulfide bonds between cysteine residues located in the luminal vestibule of the proton pumps, leading to irreversible inhibition of the gastric proton pumps [5]. Rabeprazole is a second‐generation PPI that inactivates the gastric pump through covalent binding, causing a rapid and sustained inhibition of intracellular proton efflux, as well as raising the extracellular pH [6,7]
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