Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells

Abstract

The authors show that p53 helps cancer cells survive serine depletion by coordinating metabolic remodelling; a diet lacking serine slowed tumour growth in mice, with p53-null tumours showing greatest sensitivity to serine starvation. The tumour suppressor p53 functions in a number of stress-response pathways. Karen Vousden and colleagues now report that p53 also helps cancer cells to survive conditions of serine depletion by limiting proliferation and channeling serine metabolism to glutathione production and reactive oxygen species limitation. Cells that lack p53 fail to undergo these adaptations and are much more vulnerable to serine depletion. These findings were exploited to demonstrate that a diet lacking serine can reduce the growth of p53-deficient tumours in a mouse model. This work suggests that serine depletion — by removal from the diet, enzymatic depletion or some other means — is worthy of further investigation as a possible therapeutic approach. Cancer cells acquire distinct metabolic adaptations to survive stress associated with tumour growth and to satisfy the anabolic demands of proliferation. The tumour suppressor protein p53 (also known as TP53) influences a range of cellular metabolic processes, including glycolysis1,2, oxidative phosphorylation3, glutaminolysis4,5 and anti-oxidant response6. In contrast to its role in promoting apoptosis during DNA-damaging stress, p53 can promote cell survival during metabolic stress7, a function that may contribute not only to tumour suppression but also to non-cancer-associated functions of p538. Here we show that human cancer cells rapidly use exogenous serine and that serine deprivation triggered activation of the serine synthesis pathway and rapidly suppressed aerobic glycolysis, resulting in an increased flux to the tricarboxylic acid cycle. Transient p53-p21 (also known as CDKN1A) activation and cell-cycle arrest promoted cell survival by efficiently channelling depleted serine stores to glutathione synthesis, thus preserving cellular anti-oxidant capacity. Cells lacking p53 failed to complete the response to serine depletion, resulting in oxidative stress, reduced viability and severely impaired proliferation. The role of p53 in supporting cancer cell proliferation under serine starvation was translated to an in vivo model, indicating that serine depletion has a potential role in the treatment of p53-deficient tumours.