Proton Pump Inhibitors Could Ameliorate Cachexia of Gastric Cancer by Down-regulating Vacuolar H+- ATPases and Disrupting PI3K/AKT/mTOR/HIF-1α/PKM2 Signaling Pathway

Abstract Objective：Our study aimed to investigate whether PPIs could alleviate cachexia of gastric cancer by inhibiting the expression of V-ATPases, downregulating the PI3K/AKT/mTOR/HIF-1α signaling pathway and then inhibiting PKM2.Methods: Human gastric cancer cell lines SGC7901, BGC823 and MKN28 were treated by PPIs or downregulated related factors, and then the expressions of PI3K/AKT/mTOR/HIF-1α/PKM2 signaling pathway, cell apoptosis, cell proliferation and cell migration were analyzed, respectively. In addition, in vivo experiments were conducted to further strengthen our conclusion. Results: Omeprazole, pantoprazole and esomeprazole could respectively inhibit the expression of V-ATPases at a concentration of 10 μg/ml in MKN28 whereas it had no significantly inhibitory effects on the expression of PKM2. Esomeprazole could enhance the inhibitory effects of rapamycin on p-mTOR at a concentration of 20 μg/ml , and could enhance the inhibitory effects of rapamycin on HIF-1α at 10 μg/ml (P<0.05). The mRNA expression of V-ATPases, PI3K, AKT, HIF-1α and PKM2 was inhibited in the SGC7901 cells pretreated previously with esomeprazole (20 μg/ml) for 24 hr. LY294002 with 10 μmol concentration could significantly inhibit protein expression of p-AKT and p-mTOR in the BGC823 cells after 48 hr treatment (P<0.05). After the expression of HIF-1α was knocked down by si-RNA in the BGC823 cell line, the expression of HIF-1 significantly decreased, and the expression of PKM2 decreased in the downstream, while the expression of p-mTOR in the upstream also was simultaneously elevated. Conclusion: PPIs might be a promising agent to alleviate cachexia of gastric cancer according to our in vitro and in vivo experiments.