Proton Pump Inhibitors Reduce Pancreatic Adenocarcinoma Progression by Selectively Targeting H+, K+-ATPases in Pancreatic Cancer and Stellate Cells
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Proton Pump Inhibitors Reduce Pancreatic Adenocarcinoma Progression by Selectively Targeting H+, K+-ATPases in Pancreatic Cancer and Stellate Cells. / Tozzi, Marco; Sørensen, Christiane E.; Magni, Lara; Christensen, Nynne M.; Bouazzi, Rayhana; Buch, Caroline M.; Stefanini, Matteo; Duranti, Claudia; Arcangeli, Annarosa; Novak, Ivana.
In: Cancers, Vol. 12, No. 3, 640, 2020.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Proton Pump Inhibitors Reduce Pancreatic Adenocarcinoma Progression by Selectively Targeting H+, K+-ATPases in Pancreatic Cancer and Stellate Cells
AU - Tozzi, Marco
AU - Sørensen, Christiane E.
AU - Magni, Lara
AU - Christensen, Nynne M.
AU - Bouazzi, Rayhana
AU - Buch, Caroline M.
AU - Stefanini, Matteo
AU - Duranti, Claudia
AU - Arcangeli, Annarosa
AU - Novak, Ivana
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Cyclin D1
KW - Fibrosis
KW - K channels
KW - P-CAB
KW - Pancreatic cancer
KW - Pancreatic stellate cells
KW - Pantoprazole
KW - PDAC
KW - PH regulation
KW - STAT3
U2 - 10.3390/cancers12030640
DO - 10.3390/cancers12030640
M3 - Journal article
C2 - 32164284
AN - SCOPUS:85082195746
VL - 12
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 3
M1 - 640
ER -
ID: 239669386