ININFA   02677
INSTITUTO DE INVESTIGACIONES FARMACOLOGICAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Role of cAMP efflux mediated by MRP4 in pancreatic cancer chemoresistance
Autor/es:
YANEFF, A; SHAYO, C; DI SIERVI, N; GOMEZ, N; DAVIO, C; SAHORES, A; RODRIGUEZ-GONZALEZ, A
Reunión:
Congreso; Reunion Anual de la Sociedad Argentina de Investigaciones Clinicas (SAIC); 2018
Resumen:
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 MRP4is critical in PDAC cell proliferation, migration, tumorigenesis, 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. Western blot analysis demonstrated a significant increase in MRP4 protein levels in all treated cells. Chronic treatment with crescent doses of gemcitabine reduced sensitivity to this agent, with a significant shift in IC50 and a concomitant increment in MRP4 levels. Moreover, the addition of cAMP to BxPC3 cells activated proliferative and survival pathways, which are key in the adaptation to chemotherapy. Also, incubation with cAMP and not its metabolites was able to induce a transient increase in Calciumintracellular levels, suggesting a direct effect of extracellular cAMP on tumor cells. Collectively, our results indicate that exposure to chemotherapeutic agents induces MRP4 expression, augmenting cAMP efflux, which may act as an autocrine factor on neoplasic cells and as a paracrine factor in the tumor microenvironment. Inhibiting MRP4-cAMP transport may represent a novel therapeutic strategy to prevent or delay PDAC chemoresistance.