RT Journal Article SR Electronic T1 IDENTIFICATION OF MRP4/ABCC4 AS A TARGET FOR REDUCING THE PROLIFERATION OF PANCREATIC DUCTAL ADENOCARCINOMA CELLS BY MODULATING THE cAMP EFFLUX JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.118.115444 DO 10.1124/mol.118.115444 A1 Alejandro Carozzo A1 Agustin Yaneff A1 Natalia Gomez A1 Nicolas Di Siervi A1 Ana Sahores A1 Federico Diez A1 Alejandra I. Attorresi A1 Angela Rodriguez-Gonzalez A1 Federico Monczor A1 Natalia Fernandez A1 Martin Abba A1 Carina Shayo A1 Carlos Davio YR 2019 UL http://molpharm.aspetjournals.org/content/early/2019/05/01/mol.118.115444.abstract AB Pancreatic cancer is one of the most lethal types of tumors with no effective therapy available, is currently the third leading cause of cancer in developed countries and is predicted to become the second deadliest cancer in the U.S. by 2030. Due to the marginal benefits of current standard chemotherapy, the identification of new therapeutic targets is greatly required. Considering that cAMP pathway is commonly activated in pancreatic ductal adenocarcinoma (PDAC) and its premalignant lesions, we aim to investigate the MRP4-dependant cAMP extrusion process as a cause of increased cell proliferation in human PDAC cell lines. Our results from in silico analysis indicate that MRP4 expression may influence PDAC patient outcome, thus high MRP4 levels could be indicators of poor survival. In addition, we performed in vitro experiments and identified an association between higher MRP4 expression levels and more undifferentiated and malignant models of PDAC and cAMP extrusion capacity. We studied the anti-proliferative effect and the overall cAMP response of three MRP4 inhibitors - probenecid, MK571 and ceefourin-1- in PDAC in vitro models. Moreover, MRP4 specific silencing in PANC-1 cells reduced cell proliferation (p<0.05), while MRP4 overexpression in BxPC-3 cells significantly incremented their growth rate in culture (p<0.05). MRP4 pharmacological inhibition or silencing abrogated cell proliferation through the activation of the cAMP/Epac/Rap1 signaling pathway. Also, extracellular cAMP reverted the anti-proliferative effect of MRP4 blockade. Our data highlight the MRP4-dependent cAMP extrusion process as a key participant in cell proliferation, indicating that MRP4 could be an exploitable therapeutic target for PDAC.SIGNIFICANCE STATEMENT ABCC4/MRP4 is the main transporter responsible for cAMP efflux. In this work, we show that MRP4 expression may influence PDAC patient outcome, and identify an association between higher MRP4 expression levels and more undifferentiated and malignant <I>in vitro</I> models of PDAC. Findings prove the involvement of MRP4 in PDAC cell proliferation through a novel extracellular cAMP mitogenic pathway, and further support MRP4 inhibition as a promising therapeutic strategy for PDAC treatment.