Role of PKM2 in directing the metabolic fate of glucose in cancer: a potential therapeutic target

Many of the hallmarks of cancer are not inherently unique to cancer, but rather represent a re-enactment of normal host responses and activities. A vivid example is aerobic glycolysis ('Warburg effect'), which is used not only by cancer cells but also by normal cells that undergo rapid proliferation. A common feature of this metabolic adaptation is a shift in the expression of pyruvate kinase (PK) isoform M1 to isoform M2. Here, we highlight the key role of PKM2 in shifting cancer metabolism between ATP production and biosynthetic processes. Since anabolic processes are highly energy dependent, the fate of glucose in energy production versus the contribution of carbon in biosynthetic processes needs to be finely synchronised. PKM2 acts to integrate cellular signalling and allosteric regulation of metabolites in order to align metabolic activities with the changing needs of the cell. The central role of PKM2 in directing the flow of carbon between catabolic (ATP-producing) and anabolic processes provides unique opportunities for extending the therapeutic window of currently available and/or novel anti-neoplastic agents.