Role of cAMP efflux mediated by MRP4 in pancreatic cancer chemoresistance

DI SIERVI N; CAROZZO A; DAVIO C; YANEFF A; SHAYO C; SAHORES A; GÓMEZ N

Mar del Plata

Congreso; LXIII Reunión Científica anual de la Sociedad Argentina de Investigación Clínica; 2018

SAIC

Pancreatic ductal adenocarcinoma (PDAC) ranks among the most lethal of human malignancies. This is due to several factors: lack of early diagnosis, extensive local tumor invasion, early systemic dissemination, and extremely poor response to chemotherapy. Thus, there is an urgent need to improve the therapeutic of PDAC. Previous results from our laboratory indicate that cAMP efflux mediated by MRP4 is critical in PDAC cell proliferation, migration, tumorigenicity, and tumor growth rate. Therefore, the inhibition of MRP4 should be considered an alternative strategy for pancreatic cancer treatment, either alone or combined with chemotherapeutic agents. In this study, we hypothesized that the efflux of cAMP by MRP4 could be responsible of an adaptive advantage, critical in the development of chemoresistance. We treated BxPC-3 human pancreatic cancer cells with clinically used chemotherapeutic drugs which are not substrates of MRP4 (10μM gemcitabine, 50μM 5-fluorouracil, or 5μM paclitaxel; 24 h). Western blot analysis demonstrated a significant increase in MRP4 protein levels in all treated cells (p