Expression and Function of H + /K + ‐ATPases in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and novel treatments are needed. Acid/base homeostasis and transport is altered in cancer cells, and this favors cellular proliferation, invasion, metastasis and resistance to chemotherapy (1). Our studies have shown that pancreatic ducts express gastric and non‐gastric H + /K + ‐ATPases, which normally have a physiological role in pancreatic ducts (2). The aim of the present study was to investigate whether the proton pumps are expressed and functional in PDAC cell lines and whether proton pump inhibitors (PPIs) can affect cancer progression. Here we used several PDAC cell lines (AsPC‐1, BxPC‐3, Capan‐1, MiaPaCa‐2, Panc‐1) and normal human duct cell line (HPDE) and assayed for gastric HKα1, non‐gastric HKα2 and HKβ subunits (ATP4A; ATP12A; ATP4B). Quantitative PCR revealed varied expression of ATP4A and down‐regulation of ATP12A on mRNA level of cancer cell lines. Western blot analysis indicated that the HKα1 protein expression was down‐regulated, while the HKα2 was up‐regulated in some PDAC cells. The protein expression was verified by immunocytochemistry. Furthermore, BrdU assay showed that PPIs, omeprazole (1 and 10 µM) and SCH28080 (10 and 100 µM), inhibited cell proliferation by up to 50% in PDAC compared to HPDE cells. Cell migration rate, assessed in Boyden chamber, was decreased up to 75% by high concentrations of PPIs. In conclusion, these data provide the first evidence that the H + /K + ‐ATPases are involved in PDAC progression and that PPIs attenuate cell proliferation and migration. Therefore, use of PPIs in pancreas cancer therapy can be considered. Novo Nordisk and Lundbeck Foundations; Danish Natural Sciences Research Council