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

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.

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Figure 1: p53 promotes cell survival and proliferation during serine starvation in vitro and in vivo.
Figure 2: Serine starvation differentially changes energy metabolism in p53 +/+ and p53 −/− cells.
Figure 3: Serine starvation causes recruitment of p53 to the p21 promoter and activation of a transient p21-dependent G1 arrest.
Figure 4: p53-p21 activation allows serine-deprived cells to synthesize GSH in preference to nucleotides.

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Acknowledgements

This work was funded by Cancer Research UK. C.R.B. is a recipient of a Rubicon Fellowship from the Netherlands Organisation for Scientific Research. The authors thank A. Vigneron, B. Chaneton, M. O’Prey, E. Cheung, D. Athineos, G. Kalna, G. Mackay and B. Ludwig for advice and technical assistance.

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Contributions

K.H.V. and O.D.K.M. conceived the project and wrote the manuscript with C.R.B.’s help. C.R.B. and L.Z. performed and optimized LC–MS, C.R.B. and O.D.K.M. analysed LC–MS raw data. E.G. contributed to the design and interpretation of LC–MS experiments. K.B. and S.M.M. carried out the xenograft experiment, from which K.B. and O.D.K.M. analysed the data. O.D.K.M. performed all other experiments and data analysis. All the authors discussed the results and commented on the manuscript.

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Correspondence to Karen H. Vousden.

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The authors declare no competing financial interests.

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Maddocks, O., Berkers, C., Mason, S. et al. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493, 542–546 (2013). https://doi.org/10.1038/nature11743

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