Abstract

Functions of Metabolism in Cancer

Dimitrios Anastasiou, Programme Leader, MRC National Institute For Medical Research

Solid tumours are thought to develop over a long period of time, the later stages of which are associated with increased proliferation. One function of altered metabolism in cancer is to support this hyperproliferation phenotype by promoting the biosynthesis of macromolecules. Concomitantly, though, analyses of genetic lesions that occur early during cancer development indicate that metabolic reprogramming may precede the need for increased proliferation, suggesting additional functions of metabolism in tumorigenesis. We have shown that the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2) mediates metabolic changes that help cancer cells withstand oxidative stress. PKM2 is expressed in a large spectrum of solid tumours and in some normal tissues. Unlike its highly homologous alternatively spliced variant PKM1, PKM2 can be inhibited by reactive oxygen species (ROS) to promote utilisation of glucose for antioxidant responses. Abrogation of this homeostatic mechanism by expression of a ROS-insensitive mutant or small molecule activators of PKM2 increase sensitivity of cells to oxidative stress and inhibit xenograft tumour growth in mice. These studies suggest that metabolic reprogramming in cancer, in this case through expression of a ROS-responsive glycolytic enzyme isoform, can function as a defence mechanism against stress. The implications of these observations for the design of strategies to interfere with glycolytic metabolism in cancer and metabolic disease will be discussed.