p53 Is Required for the Metabolic Response to Serine Depletion

To support the high rates of proliferation necessary for tumor growth, cancer cells undergo metabolic reprogramming and increase aerobic glycolysis through the Warburg effect. The tumor suppressor p53 has been implicated in the regulation of several metabolic processes, including glycolysis, oxidative phosphorylation, and the antioxidative response, and enhances cell survival following glucose deprivation. Maddocks and colleagues found that p53 also modulated the metabolic stress response to depletion of serine, which was rapidly consumed by cancer cells. Although removal of this nonessential amino acid diminished the proliferation of p53-expressing cancer cells and xenograft tumors, this defect was more pronounced with TP53 deficiency. In cells that were wild-type for p53, serine deprivation decreased glycolysis, activated the serine synthesis pathway, and triggered an increase in tricarboxylic acid (TCA) cycle flux, which was reversed over time. Additionally, serine starvation resulted in p53 activation and induction of p21-dependent cell-cycle arrest in wild-type cells; this transient arrest promoted flux of available serine into synthesis of reduced glutathione (GSH), a cellular antioxidant, thus limiting reactive oxygen species (ROS) accumulation and increasing cell survival. In contrast, TP53-null cells exhibited sustained TCA flux and higher levels of oxygen consumption under conditions of serine starvation compared with wild-type cells. Furthermore, cells lacking p53 failed to initiate G1-phase arrest and were unable to maintain GSH synthesis, resulting in loss of antioxidant capacity and elevated intracellular ROS. Addition of exogenous pyruvate and either GSH or the antioxidant N-acetyl cysteine rescued proliferation in serine-starved TP53-null cells, indicating that both decreased glycolysis and augmented ROS accumulation are responsible for increased sensitivity to serine deprivation in the absence of p53. These results further establish p53 as an important mediator of metabolic stress responses and suggest that serine depletion may reduce the growth of TP53-deficient tumors.

Maddocks OD, Berkers CR, Mason SM, Zheng L, Blyth K, Gottlieb E, et al. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 2012 Dec 16 [Epub ahead of print].

Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.