Nature Journal Club

Gerry Melino

Medical Research Council, University of Leicester, UK

A cancer biologist weighs up p53, metabolism and cancer.

The classic tumour-suppressor gene, p53, plays a pivotal part in halting the cell cycle and inducing programmed cell death in response to DNA damage. However, recent data suggest that it also has a role in cellular metabolism. I have become intrigued by the possibility that the inactivation of p53, which is common in tumours, also contributes to a cellular shift from a metabolic pathway called oxidative phosphorylation to a less efficient one known as glycolysis. This shift, called the Warburg effect, is characteristic of tumour cells.

Two papers shed light on this possibility. Both show that GLS2, an enzyme involved in oxidative phosphorylation, is regulated by p53 under stressed and non-stressed conditions. Arnold Levine at the Institute for Advanced Study in Princeton, New Jersey, and his colleagues also show that GLS2 increases the respiration rate in the cell’s energy-producing organelles, the mitochondria, resulting in increased generation of the cell’s fuel source, ATP (W. Hu et al. Proc. Natl Acad. Sci. USA 107, 7455–7460; 2010).

Meanwhile, Carol Prives at Columbia University in New York and her co-workers find that GLS2 expression is lost, or greatly decreased, in liver cancers, and that overexpression of GLS2 reduces the number of tumour cell colonies formed (S. Suzuki et al. Proc. Natl Acad. Sci. USA 107, 7461–7466; 2010). The results reveal that GLS2 is an important component in mediating a novel function of p53: the regulation of energy metabolism.

This is an attractive and provocative hypothesis. There are some understandable discrepancies in the data, which suggests that additional mechanisms may be contributing to the metabolic changes. Nevertheless, these two papers provide a potential mechanism linking the metabolic and genetic characteristics of tumours

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