{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T18:47:34Z","timestamp":1793040454317,"version":"4.5.0"},"reference-count":57,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,3,10]],"date-time":"2020-03-10T00:00:00Z","timestamp":1583798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["1072301001"],"award-info":[{"award-number":["1072301001"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003554","name":"Lundbeckfonden","doi-asserted-by":"publisher","award":["R173-2014-1462"],"award-info":[{"award-number":["R173-2014-1462"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008394","name":"Natur og Univers, Det Frie Forskningsr\u00e5d","doi-asserted-by":"publisher","award":["DFF-4002-00162"],"award-info":[{"award-number":["DFF-4002-00162"]}],"id":[{"id":"10.13039\/100008394","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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\u2014all 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.<\/jats:p>","DOI":"10.3390\/cancers12030640","type":"journal-article","created":{"date-parts":[[2020,3,12]],"date-time":"2020-03-12T04:13:57Z","timestamp":1583986437000},"page":"640","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Proton Pump Inhibitors Reduce Pancreatic Adenocarcinoma Progression by Selectively Targeting H+, K+-ATPases in Pancreatic Cancer and Stellate Cells"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2576-0183","authenticated-orcid":false,"given":"Marco","family":"Tozzi","sequence":"first","affiliation":[{"name":"Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6814-1166","authenticated-orcid":false,"given":"Christiane E.","family":"S\u00f8rensen","sequence":"additional","affiliation":[{"name":"Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark"},{"name":"Section of Clinical Oral Microbiology, Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara","family":"Magni","sequence":"additional","affiliation":[{"name":"Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nynne M.","family":"Christensen","sequence":"additional","affiliation":[{"name":"Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rayhana","family":"Bouazzi","sequence":"additional","affiliation":[{"name":"Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline M.","family":"Buch","sequence":"additional","affiliation":[{"name":"Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4556-5166","authenticated-orcid":false,"given":"Matteo","family":"Stefanini","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, 50134 Florence, Italy"},{"name":"DI.V.A.L. Toscana SRL, 50019 Sesto Fiorentino, Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Duranti","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annarosa","family":"Arcangeli","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8917-8010","authenticated-orcid":false,"given":"Ivana","family":"Novak","sequence":"additional","affiliation":[{"name":"Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21590","article-title":"Cancer statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"CA Cancer J. 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