Journal
CANCERS
Volume 12, Issue 3, Pages -Publisher
MDPI
DOI: 10.3390/cancers12030640
Keywords
pancreatic cancer; pH regulation; K+ channels; pantoprazole; pancreatic stellate cells; fibrosis; cyclin D1; STAT3; PDAC; P-CAB
Categories
Funding
- Novo Nordisk Foundation [NNF13OC0007353]
- Lundbeck Foundation [R173-2014-1462]
- Independent Research Fund Denmark/Natural Sciences and Medical Sciences [DFF-4002-00162, DFF-8020-00254B, 00254B]
- EU TALENT program under the Marie Sklodowska Curie grant [801199]
- Marie Curie Actions (MSCA) [801199] Funding Source: Marie Curie Actions (MSCA)
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Pancreatic duct cells are equipped with acid/base transporters important for exocrine secretion. Pancreatic ductal adenocarcinoma (PDAC) cells may utilize such transporters to acidify extracellular tumor microenvironment, creating a niche favoring cell proliferation, fibrosis and resistance to chemotherapy-all contributing to the notoriously bad prognosis of this disease. Here, we report that gastric and non-gastric H+, K+-ATPases (coded by ATP4A and ATP12A) are overexpressed in human and murine pancreatic cancer and that we can target them specifically with proton pump inhibitors (PPIs) and potassium-competitive acid blockers (P-CABs) in in vitro models of PDAC. Focusing on pantoprazole, we show that it significantly reduced human cancer cell proliferation by inhibiting cellular H+ extrusion, increasing K+ conductance and promoting cyclin D1-dependent cell cycle arrest and preventing STAT3 activation. Pantoprazole also decreased collagen secretion from pancreatic stellate cells. Importantly, in vivo studies show that pantoprazole treatment of tumor-bearing mice reduced tumor size, fibrosis and expression of angiogenic markers. This work provides the first evidence that H+, K+-ATPases contribute to PDAC progression and that these can be targeted by inhibitors of these pumps, thus proving a promising therapeutic strategy.
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