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

Research output: Contribution to journal › Journal article › Research › peer-review

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.

In: Cancers, Vol. 12, No. 3, 640, 2020.

Research output: Contribution to journal › Journal article › Research › peer-review

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, vol. 12, no. 3, 640. https://doi.org/10.3390/cancers12030640

APA

Tozzi, M., Sørensen, C. E., Magni, L., Christensen, N. M., Bouazzi, R., Buch, C. M., 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, 12(3), [640]. https://doi.org/10.3390/cancers12030640

Vancouver

Tozzi M, Sørensen CE, Magni L, Christensen NM, Bouazzi R, Buch CM et al. 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. In: Cancers. 2020 ; Vol. 12, No. 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