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

Maddocks, O.D.K. , Berkers, C.R., Mason, S.M., Zheng, L., Blyth, K. , Gottlieb, E. and Vousden, K.H. (2013) Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature, 493(7433), pp. 542-546. (doi: 10.1038/nature11743)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Blyth, Professor Karen and Berkers, Dr Celia and Zheng, Mr Liang and Maddocks, Professor Oliver and Gottlieb, Professor Eyal and Vousden, Karen and Mason, Miss Susan
• Authors: Maddocks, O.D.K., Berkers, C.R., Mason, S.M., Zheng, L., Blyth, K., Gottlieb, E., and Vousden, K.H.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature
• Publisher: Nature Publishing Group
• ISSN: 0028-0836
• Published Online: 16 December 2012