Suppression of vacuolar-type ATPase and induction of endoplasmic reticulum stress by proton pump inhibitors.

Abstract

Proton pump inhibitors (PPIs), such as esomeprazole, pantoprazole, dexlansoprazole, and rabeprazole, are one of the most commonly prescribed medications. Several studies have linked the long-term use of PPIs to a potentially increased risk of gastric cancer. Therefore, this study aimed to determine the underlying mechanism of PPI-mediated gastric cancer. Lysosomes were isolated using immunoprecipitation. The inhibition of vacuolar-type ATPase (V-ATPase) by PPIs was assayed using a PiColorLock Gold Phosphate Detection System. PPI-induced lysosomal stress was analyzed using transcription factor EB (TFEB) nuclear translocation. PPI-induced endoplasmic reticulum (ER) stress was analyzed using the expression of protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). Finally, reactive oxygen species (ROS) removal was determined using the activity of superoxide dismutase (SOD). PPIs caused a 70% inhibition of V-ATPase activity at 20 μM, leading to lysosomal stress through TFEB nuclear translocation; ER stress by inducing the expression of PERK, IRE1, and ATF6; and enhanced SOD activity for ROS removal. The long-term use of PPIs inhibits lysosomal V-ATPase, leading to ER stress and ROS accumulation, which may result in an increased risk of gastric cancer. Because lysosomes and the ER are common organelles in cells, physicians prescribing PPIs for gastroesophageal reflux and peptic ulcer diseases should pay more attention to the general effects of these agents on the human body.