IMPLICATIONS OF THE MRP4-MEDIATED EXCLUSION OF cAMP ON CELL PROLIFERATION AND DIFFERENTIATION IN PANCREATIC DUCTAL ADENOCARCINOMA MODELS

CAROZZO ALEJANDRO; DIEZ FEDERICO; COPSEL SABRINA; SHAYO CARINA; FERNADEZ NATALIA; DAVIO CARLOS

Simposio; South American spring Symposium in Signal Trasducction and Molecular Medicine. (SISTAM 2012).; 2012

Pancreatic ductal adenocarcinoma (PDAC) represents more than 85% of pancreatic cancers and are the 4th leading cause of cancer death, largely due to its high aggressiveness, invasiveness and resistance to chemotherapeutic agents. Several reports suggest that cAMP is involved in the processes of proliferation and differentiation of both normal and malignant cells. The intracellular levels (icAMP) of this cyclic nucleotide results from the balance between its production, degradation and exclusion. This latter process is mediated by members of the multidrug resistance-associated protein family (MRPs), particularly MRP4, 5 and 8. We and others have postulated MRP4 as a new therapeutic target candidate in leukemia for its ability to regulate intracellular levels of cAMP and in consequence proliferation and cellular differentiation processes. In order to establish MRP4 as a potential therapeutic target in pancreatic cancer, we aimed to evaluate the relationship between the cAMP-exclusion and MRP4 involvement in PDAC cell lines (HPAF-II, BxPC-3, PANC-I). Pancreatic ductal adenocarcinoma cell lines exclude cAMP in a concentration-dependent manner in response to stimuli that increase its production, thus contributing to the regulation of its intracellular levels. This exclusion process is sensitive to Probenecid, suggesting that it is mediated by multidrug resistance-associated proteins (MRPs). All PDAC cell lines tested expressed MRP4 and presented a correlation between the degree of malignancy and differentiation grade with the MRP4-expression levels and its cAMP-exclusion capacity. This exclusion process occurs even in basal conditions and its inhibition by probenecid determines a decrease of cell proliferation and a G1 arrest of the cell cycle.