IDENTIFICATION OF MRP4/ABCC4 AS A TARGET FOR REDUCING THE PROLIFERATION OF PANCREATIC DUCTAL ADENOCARCINOMA CELLS BY MODULATING THE cAMP EFFLUX

CAROZZO, ALEJANDRO; YANEFF, AGUSTIN; GOMEZ, NATALIA; DI SIERVI, NICOLAS; SAHORES, ANA; DIEZ, FEDERICO; ATTORRESI, ALEJANDRA I.; RODRIGUEZ-GONZALEZ, ANGELA; MONCZOR, FEDERICO; FERNANDEZ, NATALIA; ABBA, MARTIN; SHAYO, CARINA; DAVIO, CARLOS

MOLECULAR PHARMACOLOGY

AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS

Lugar: Baltimore; Año: 2019

0026-895X

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