PO-222 Targeting cancer cell metabolism in melanomas: metabolic profiling and 3-bromopyruvate sensitivity screening

Abstract

IntroductionMetabolic reprogramming in cancer cells is associated with a switch to glycolysis as the main energy producing pathway, even in the presence of oxygen, a mechanism known as the Warburg effect. The rely of cancer cells in glycolysis is often associated with overexpression of metabolism-related proteins, such as monocarboxylate transporters (MCTs). Recently, MCT1 has been identified as the carrier of 3-bromopyruvate (3 BP), a synthetic derivative of pyruvate and lactate analogue that exerts a potent antitumoral activity, by inhibiting cancer cell energy metabolism. Melanoma is the most aggressive skin cancer with about 40%–60% of cases presenting the BRAF V600E mutation. BRAF mutations make cells energetically dependent on Warburg effect. In this context, the use of 3 BP associated with the overexpression of MCT1 could be a new effective strategy in treatment of melanomas. Furthermore, the acquired resistance of melanomas to BRAF V600E inhibitor, vemurafenib, remains elusive and the study of the metabolic alterations involved in vemurafenib resistance may pave the way for the exploitation of alternative therapeutic approaches.Material and methodsImmunocytochemical and western blotting expression of MCT1/2/4, CD147, CD44, CAIX and GLUT1, along with quantification of extracellular levels of glucose and lactate were evaluated in a large panel of melanoma cell lines, including vemurafenib-resistant cells. Also, a screening for sensitivity to 3 BP was performed.Results and discussions1205Lu, SK-MEL-103 and WM164 presented a preferentially glycolytic metabolic profile while SK-MEL-173 presented an oxidative profile. A375, SK-MEL-103 and UACC-62 showed greater sensitivity to 3 BP treatment, while SK-MEL-19, SK-MEL-173, WM35 and WM793 showed less sensitivity to the drug. Considering the expression of MCT1, it was observed that the cell lines more sensitive to 3 BP presented MCT1 expression while the cell lines with higher resistance to 3 BP showed decreased expression of MCT1. All melanoma cell lines with vemurafenib resistance presented MCT1 expression. When compared to parental cell lines, A-375-R and SKMEL-19-R presented a decrease in sensitivity to 3 BP treatment, while SKMEL-28-R and WM164-R presented an increase in sensitivity to 3 BP.ConclusionThe results obtained support the hypothesis that MCT1 expression may be related to the sensitivity profiles associated with 3 BP treatment in melanomas. Additional studies are needed to further explore the role of melanoma metabolism with acquired resistance to vemurafenib.