Cyclic AMP extrusion abrogation inhibits PANC-1 cell proliferation through activation of EPAC/RAP1 pathway

AGUSTÍN YANEFF; ALEJANDRO CAROZZO; CARLOS DAVIO; ALEJANDRA ATORRESI; NATALIA GÓMEZ; NICOLÁS DI SIERVI; CARINA SHAYO

Mar del Plata

Congreso; LXI Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2016

Sociedad Argentina de Investigación Clínica

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer with a 5-year survival rate of 4%. This is caused by its high resistance to conventional therapies, its delayed diagnosis and high metastatic potential. Previously, we established a correlation between MRP4 expression and the level of differentiation, malignancy and cAMP extrusion capacity of PDAC cells, thus proposing it as a possible target for this disease. Our working hypothesis is that the antiproliferative effects of MRP4 inhibition are a consequence of the modulation of cAMP extrusion. This work concentrates in unraveling which cAMP pathways are leading this process. The temporal progression of intracellular cAMP (i-cAMP) induced response was performed using FRET assays in PANC-1 cells transfected with a plasmid encoding a cAMP molecular sensor (Epac-SH187). MRP4 inhibition using MK571 evoked a significant increase in i-cAMP within the first minutes of measurement after stimulation with Isoproterenol 10 uM (p