David Jayne, email: d.g.jayne@leeds.ac.uk
The majority of solid cancers show a preference for aerobic glycolysis rather than oxidative phosphorylation as a means of deriving energy from glucose. This is irrespective of the prevailing tissue oxygen tension, and a characteristic known as the Warburg effect. Although aerobic glycolysis is inferior to oxidative phosphorylation in terms of the amount of ATP generated per molecule of glucose, it is believed to bestow certain advantages to cancer cells allowing them to survive in the local tumour microenvironment. Aerobic glycolysis is a means of rapid ATP generation, which may be beneficial to the rapidly proliferating cancer cell. Lactic acid is produced as an end-product of glycolysis, which is exported out of the cell resulting in an acidic extracellular milieu that may be favourable for invasion but detrimental to the host immune response. The switch away from oxidative phosphorylation may also help to prevent excessive free radical formation in the presence of diminished oxygen supply, and so prevent cancer cell apoptosis.
Current research is focused on the pyruvate dehydrogenase (PDH) enzyme system, which controls the switch between aerobic glycolysis and oxidative phosphorylation in normal and cancer cells. PDH catalyses the conversion of Pyruvate to Acetyl CoA, which subsequently enters the citric acid cycle and fuels oxidative phosphorylation. Down-regulation or inhibition of PDH favours aerobic glycolysis. Tissue microarray techniques have confirmed that aerobic glycolysis is up-regulated in colorectal cancer and that this is probably brought about by differential up-regulation of pyruvate dehydrogenase kinases (PDK1-4), the natural inhibitors of PDH. In vitro work using a variety of colorectal cancer cell lines has shown that inhibition of the PDK1-4 by Dichloroacetate results in up-regulation of PDH activity with a switch to oxidative phosphorylation and accompanying decreased cell proliferation, cell viability, G2 cell cycle arrest, and increased apoptosis. The PDH/PDK system would therefore seem to be a suitable metabolic target for cancer therapy.
A studentship is offered to pursue research into the role of the PDH/PDK system as a therapeutic target for cancer. Future work will concentrate on confirming the potential of the PDH/PDK system as a therapeutic target, assessing the effects of PDK1-4 siRNA knock down on cancer cell function, and developing an animal model for evaluating the in vivo effects of PDK1-4 knock-down/inhibition.