The time has come to pull renal cancer’s sweet tooth

The metabolic theory of cancer is based on cancer’s unique suppression of mitochondrial glucose oxidation and upregulation of cytosolic glycolysis, first identified by Otto Warburg nearly 100 years ago (1). This “Warburg effect” has been shown to be driven by numerous mechanisms including growth factor signalling, oncogene expression, metabolic enzyme mutation and regulation of factors that control mitochondrial homeostasis (2). Central to this metabolic remodelling is the inhibition of the mitochondrial pyruvate dehydrogenase complex (PDC), which is the key gate-keeping enzyme linking glycolysis to mitochondrial glucose oxidation. PDC converts the end-product of glycolysis, pyruvate, into acetyl-CoA which is then fed into the Krebs’ cycle in mitochondria to complete glucose oxidation (Figure 1A) (3). PDC activity is decreased by an inhibitory phosphorylation in Serine 293 by the mitochondrial enzyme pyruvate dehydrogenase kinase (PDK) although an additional inhibitory tyrosine phosphorylation by tyrosine kinases may contribute (2). Additional reasons resulting in decreased PDH activity include acetylation of the protein, for example by loss of the mitochondrial deacetylase Sirtuin3 (Sirt3); or by a decrease in mitochondrial calcium levels, which can result by the loss of a mitochondrial calcium transporter, i.e., the mitochondrial uncoupling protein 2 (UCP2) (4)