Multidrug Resistance Protein 4/ ATP binding cassette transporter 4 is overexpressed clear cell renal cell carcinoma (ccRCC)

MELANA COLAVITA, JUAN PABLO; MARIA MAY; STOYANOFF, TANIA ROMINA; GOMAZ, NATALIA; TODARO, JUAN SANTIAGO; AGUIRRE, MARIA VICTORIA; MIGNOLLI, FRANCESCO; DAVIO, CARLOS; RODRIGUEZ, JUAN PABLO

Mar del Plata

Jornada; LXI ANNUAL MEETING ARGENTINE SOCIETY FOR CLINICAL INVESTIGATION (SAIC) - LXIV ANNUAL MEETING ARGENTINE SOCIETY OF IMMUNOLOGY (SAI) - XLVIII ANNUAL MEETING ARGENTINE SOCIETY OF EXPERIMENTAL PHARMACOLOGY (SAFE); 2016

SAFE - SAIC - SAI

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma, which is the most prevalent kidney cancer among adults, accounting for approximately 89% of all diagnosed cases. Presently, there is a paucity of effective therapies designed to target ccRCC effectuating long-term durable response in patients with advanced disease. In addition, there is a lack of molecular markers that can be remedially targeted, showing tumor-specific inhibition. Recently, it was demonstrated that besides playing a role in drug-resistant tumoral cell lines, multidrug resistance protein 4 (MRP4/ABCC4) regulates cell proliferation and differentiation through the endogenous MRP4/ABCC4 substrate, cAMP. Both features make it an attractive option to use it as a therapeutic target. Up to now, it has not been reported that MRP4/ABCC4 is involved in the biology of renal cell carcinoma. Thus, the objective of this work was to determine the level of expression of this protein in renal carcinoma and its implication in cell proliferation. Using quantitative PCR, we detected an average 30-fold increase in mRNA of MRP4/ABCC4 in tumors, compared to a distal portion of kidney taken as control (n=27). Westernblott analysis confirmed the overexpression of this protein and its localization was studied by immunohistochemistry. We detected an aberrant expression of MRP4/ABCC4 in renal tumor cells, localized in concentrated foci. In order to determine whether the intracellular cAMP concentration interferes in cell proliferation, functional studies were developed using the cell line Caki-2. Treatment of these cells with Forskolin and MK571 resulted in significant inhibition of cell proliferation. In the best of our knowledge, this work first informs the overexpression of this protein in ccRCC. These results and further functional studies, in renal cell lines, may validate MRP4/ABCC4 as a possible therapeutic target in ccRCC.