Proton pump inhibitor selectively suppresses proliferation and restores the chemosensitivity of gastric cancer cells by inhibiting STAT3 signaling pathway.

BACKGROUNDS AND AIMS: Recent studies reported that pretreatment of proton pump inhibitors (PPIs) induced sensitization to chemotherapeutic agents in several cancer cells. The devastating effects of PPIs on tumor cells were discovered and raised great interests; therefore we designed the following experiments to fully explain the direct antitumor effects of PPIs.
METHODS: We compared the viability of gastric cancer cells and epithelia cells in buffered and unbuffered culture conditions with PPZ treatment by WST-8 assay. The sensitivity to cisplatin of gastric cancer cells with/without PPZ pretreatment was assessed by IC50 calculation and Annexin V/PI assay. The secretion of IL-6 was detected by ELISA. Western blot analysis and real time RT-PCR were used to evaluate the expression and activation of STAT3 and its downstream targets.
RESULTS: PPZ selectively exhibited a dose-dependent cytotoxic effect of gastric cancer cells in acidic unbuffered medium. Low dose of PPZ pretreatment (20 μg/mL) enhanced the sensitivity to cisplatin in gastric cancer cells. PPZ induced cell apoptosis and reduced the secretion of the pro-inflammatory cytokine IL-6 specifically in gastric cancer cells, but had no effect on the epithelia cells. Consequently, the activation of STAT3, not the total amount, was suppressed by PPZ in gastric cancer cells. The downstream targets of STAT3, c-Myc, cyclin D1 and Bcl-2 were also down-regulated.
CONCLUSION: PPZ causes gastric cancer cell death by induction of apoptosis and its mechanism of action is mediated in part via the inhibition of IL-6/STAT3 pathway.