Pyruvate dehydrogenase kinase expression profile is a biomarker for cancer sensitivity to dichloroacetate-mediated growth inhibition.

Abstract

BackgroundCancer cells favour glycolysis and lactate production over mitochondrial metabolism despite the presence of oxygen (the Warburg effect). Increased pyruvate dehydrogenase kinase (PDK) activity contributes to this glycolytic phenotype. Dichloroacetate (DCA) is a PDK inhibitor with anti-cancer potential that inhibits all four isoforms of PDK but with differing potencies, thus expression of different isoforms may determine sensitivity to DCA. MethodsThe association of sensitivity to growth inhibition by DCA, on-target effects of DCA and expression of all four isoforms of PDKs in a range of epithelial cancer cell lines was investigated in vitro and in vivo. ResultsDCA inhibited growth of cancer cells in vivo and in vitro, reduced pyruvate dehydrogenase phosphorylation and reduced lactate production. The magnitude of the effect of DCA on growth was variable and correlated with the PDK expression profiles of the cells, with low expression of PDK3 (highest Ki for DCA) conferring the highest sensitivity towards DCA. PDK2 siRNA-knockdown inhibited growth to a similar extent to DCA, whilst PDK3 knockdown significantly increased sensitivity to DCA. ConclusionThe PDK expression profile is a potential biomarker for sensitivity to DCA, and should be considered when translating PDK inhibitors into clinical use.