Abstract
BackgroundAdvances in melanoma treatment through targeted inhibition of oncogenic BRAF are limited owing to the development of acquired resistance. The involvement of BRAFV600E in metabolic reprogramming of melanoma cells provides a rationale for co-targeting metabolism as a therapeutic approach.MethodsWe examined the effects of dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase, on the growth and metabolic activity of human melanoma cell lines. The combined effect of DCA and the BRAF inhibitor vemurafenib was investigated in BRAFV600E -mutated melanoma cell lines. Vemurafenib-resistant cell lines were established in vitro and their sensitivity to DCA was tested.ResultsDCA induced a reduction in glycolytic activity and intracellular ATP levels, and inhibited cellular growth. Co-treatment of BRAFV600E-mutant melanoma cells with DCA and vemurafenib induced a greater reduction in intracellular ATP levels and cellular growth than either compound alone. In addition, melanoma cells with in vitro acquired resistance to vemurafenib retained their sensitivity to DCA.ConclusionsThese results suggest that DCA potentiates the effect of vemurafenib through a cooperative attenuation of energy production. Furthermore, the demonstration of retained sensitivity to DCA in melanoma cells with acquired resistance to vemurafenib could have implications for melanoma treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-014-0247-5) contains supplementary material, which is available to authorized users.
Highlights
Advances in melanoma treatment through targeted inhibition of oncogenic BRAF are limited owing to the development of acquired resistance
A molecular link was recognized between the RAS-RAF-MEK-ERK-MAPK pathway and the energetic-stress check-point mediated by the liver kinase B1 (LKB1)-AMP activated protein kinase (AMPK) pathway, suggesting a role of BRAFV600E in mediating resistance to energetic stress [8,9]
11 out of 12 cell lines presented with higher glycolytic rates, as indicated by higher basal glycolytic extracellular acidification rate (ECAR), showing that the Warburg effect is a general characteristic of melanoma cells
Summary
Advances in melanoma treatment through targeted inhibition of oncogenic BRAF are limited owing to the development of acquired resistance. The involvement of BRAFV600E in metabolic reprogramming of melanoma cells provides a rationale for co-targeting metabolism as a therapeutic approach. A hallmark of cancer is the reprogramming of cellular metabolism towards aerobic glycolysis. This metabolic pattern is characterized by increased glucose uptake and highly up-regulated glycolytic activity with fermentation of glucose into lactic acid instead of complete aerobic decomposition in the mitochondria. BRAFV600E was shown to mediate oncogene-induced senescence through metabolic regulation. This mechanism involves an increase in pyruvate dehydrogenase (PDH) activity through the suppression of pyruvate dehydrogenase kinase (PDK) [10]. On the basis of these findings, targeted inhibition of PDK was proposed as a therapeutic option for melanoma, with a possible synergistic effect of chemical BRAFV600E inhibitors, such as vemurafenib [10,13]
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