Proton Pump Inhibitors Reduce Pancreatic Adenocarcinoma Progression by Selectively Targeting H+, K+-ATPases in Pancreatic Cancer and Stellate Cells

Cancers

Annarosa Arcangeli¹  Matteo Stefanini¹  Claudia Duranti¹  Lara Magni²  Ivana Novak²  CarolineM. Buch²  NynneM. Christensen²  Marco Tozzi²  ChristianeE. Sørensen²  Rayhana Bouazzi² 

[1] Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, 50134 Florence, Italy;Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark;

关键词: pancreatic cancer;    ph regulation;    k⁺ channels;    pantoprazole;    pancreatic stellate cells;    fibrosis;    cyclin d1;    stat3;    pdac;    p-cab;   

DOI  :  10.3390/cancers12030640

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown