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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Standard

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.

I: Cancers, Bind 12, Nr. 3, 640, 2020.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Harvard

Tozzi, M, Sørensen, CE, Magni, L, Christensen, NM, Bouazzi, R, Buch, CM, Stefanini, M, Duranti, C, Arcangeli, A & Novak, I 2020, 'Proton Pump Inhibitors Reduce Pancreatic Adenocarcinoma Progression by Selectively Targeting H+, K+-ATPases in Pancreatic Cancer and Stellate Cells', Cancers, bind 12, nr. 3, 640. https://doi.org/10.3390/cancers12030640

APA

Tozzi, M., Sørensen, C. E., Magni, L., Christensen, N. M., Bouazzi, R., Buch, C. M., ... Novak, I. (2020). Proton Pump Inhibitors Reduce Pancreatic Adenocarcinoma Progression by Selectively Targeting H+, K+-ATPases in Pancreatic Cancer and Stellate Cells. Cancers, 12(3), [640]. https://doi.org/10.3390/cancers12030640

Vancouver

Tozzi M, Sørensen CE, Magni L, Christensen NM, Bouazzi R, Buch CM o.a. Proton Pump Inhibitors Reduce Pancreatic Adenocarcinoma Progression by Selectively Targeting H+, K+-ATPases in Pancreatic Cancer and Stellate Cells. Cancers. 2020;12(3). 640. https://doi.org/10.3390/cancers12030640

Author

Tozzi, Marco ; Sørensen, Christiane E. ; Magni, Lara ; Christensen, Nynne M. ; Bouazzi, Rayhana ; Buch, Caroline M. ; Stefanini, Matteo ; Duranti, Claudia ; Arcangeli, Annarosa ; Novak, Ivana. / Proton Pump Inhibitors Reduce Pancreatic Adenocarcinoma Progression by Selectively Targeting H+, K+-ATPases in Pancreatic Cancer and Stellate Cells. I: Cancers. 2020 ; Bind 12, Nr. 3.

Bibtex

@article{27142e34f26a47d1a7d4519865a5ef62,
title = "Proton Pump Inhibitors Reduce Pancreatic Adenocarcinoma Progression by Selectively Targeting H+, K+-ATPases in Pancreatic Cancer and Stellate Cells",
abstract = "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.",
keywords = "Cyclin D1, Fibrosis, K channels, P-CAB, Pancreatic cancer, Pancreatic stellate cells, Pantoprazole, PDAC, PH regulation, STAT3",
author = "Marco Tozzi and S{\o}rensen, {Christiane E.} and Lara Magni and Christensen, {Nynne M.} and Rayhana Bouazzi and Buch, {Caroline M.} and Matteo Stefanini and Claudia Duranti and Annarosa Arcangeli and Ivana Novak",
year = "2020",
doi = "10.3390/cancers12030640",
language = "English",
volume = "12",
journal = "Cancers",
issn = "2072-6694",
publisher = "M D P I AG",
number = "3",

}

RIS

TY - JOUR

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