MULTIDRUG RESISTANCE PROTEIN 4/ ATP BINDING CASSETTE TRANSPORTER 4 IS OVEREXPRESSED CLEAR CELL RENAL CELL CARCINOMA (CCRCC)

STOYANOFF, T; AGUIRRE, M; RODRIGUEZ, JP; MAY, M; MELANA COLAVITA, J; TODARO, J; GOMEZ, N; DAVIO, C; MIGNOLLI, F

Congreso; LXI REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA; 2016

Clearcell renal cell carcinoma (ccRCC) is the most common subtype of renal cellcarcinoma, which is the most prevalent kidney cancer among adults, accountingfor approximately 89% of all diagnosed cases. Presently, there is a paucity ofeffective therapies designed to target ccRCC effectuating long-term durable responsein patients with advanced disease. In addition, there is a lack of molecularmarkers that can be remedially targeted, showing tumor-specific inhibition.Recently, it was demonstrated that besides playing a role in drug-resistanttumoral cell lines, multidrug resistance protein 4 (MRP4/ABCC4) regulates cellproliferation and differentiation through the endogenous MRP4/ABCC4 substrate, cAMP.Both features make it an attractive option to use it as a therapeutic target. Upto now, it has not been reported that MRP4/ABCC4 is involved in the biology ofrenal cell carcinoma. Thus, the objective of this work was to determine the levelof expression of this protein in renal carcinoma and its implication in cellproliferation. Using quantitative PCR, we detected an average 30-fold increasein mRNA of MRP4/ABCC4 in tumors, compared to a distal portion of kidney takenas control (n=27). Western blott analysis confirmed the overexpression of thisprotein and its localization was studied by immunohistochemistry. We detected anaberrant expression of MRP4/ABCC4 in renal tumor cells, localized inconcentrated foci. In order to determine whether the intracellular cAMPconcentration interferes in cell proliferation, functional studies weredeveloped using the cell line Caki-2. Treatment of these cells with Forskolinand MK571 resulted in significant inhibition of cell proliferation.In the bestof our knowledge, this work first informs the overexpression of this protein inccRCC. These results and further functional studies, in renal cell lines, mayvalidate MRP4/ABCC4 as a possible therapeutic target in ccRCC.