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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.

References

  1. 1

    Bensaad, K. et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126, 107–120 (2006)

    CAS  Article  Google Scholar 

  2. 2

    Jiang, P. et al. p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nature Cell Biol. 13, 310–120 (2011)

    CAS  Article  Google Scholar 

  3. 3

    Matoba, S. et al. p53 regulates mitochondrial respiration. Science 312, 1650–1653 (2006)

    ADS  CAS  Article  Google Scholar 

  4. 4

    Suzuki, S. et al. Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc. Natl Acad. Sci. USA 107, 7461–7466 (2010)

    ADS  CAS  Article  Google Scholar 

  5. 5

    Hu, W. et al. Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc. Natl Acad. Sci. USA 107, 7455–7460 (2010)

    ADS  CAS  Article  Google Scholar 

  6. 6

    Budanov, A. V. et al. Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science 304, 596–600 (2004)

    ADS  CAS  Article  Google Scholar 

  7. 7

    Jones, R. G. et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 18, 283–293 (2005)

    CAS  Article  Google Scholar 

  8. 8

    Maddocks, O. D. K. & Vousden, K. H. Metabolic regulation by p53. J. Mol. Med. 89, 237–245 (2011)

    CAS  Article  Google Scholar 

  9. 9

    Rose, M. L. et al. Dietary glycine prevents the development of liver tumors caused by the peroxisome proliferator WY-14,643. Carcinogenesis 20, 2075–2081 (1999)

    CAS  Article  Google Scholar 

  10. 10

    Rose, M. L., Madren, J., Bunzendahl, H. & Thurman, R. G. Dietary glycine inhibits the growth of B16 melanoma tumors in mice. Carcinogenesis 20, 793–798 (1999)

    CAS  Article  Google Scholar 

  11. 11

    Jain, M. et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336, 1040–1044 (2012)

    ADS  CAS  Article  Google Scholar 

  12. 12

    Snell, K. The duality of pathways for serine biosynthesis is a fallacy. Trends Biochem. Sci. 11, 241–243 (1986)

    CAS  Article  Google Scholar 

  13. 13

    Snell, K. & Fell, D. A. Metabolic control analysis of mammalian serine metabolism. Adv. Enzyme Regul. 30, 13–32 (1990)

    CAS  Article  Google Scholar 

  14. 14

    Pollari, S. et al. Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis. Breast Cancer Res. Treat. 125, 421–430 (2011)

    CAS  Article  Google Scholar 

  15. 15

    Possemato, R. et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476, 346–350 (2011)

    ADS  CAS  Article  Google Scholar 

  16. 16

    Locasale, J. W. & Cantley, L. C. Genetic selection for enhanced serine metabolism in cancer development. Cell Cycle 10, 3812–3813 (2011)

    CAS  Article  Google Scholar 

  17. 17

    Ye, J. et al. Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation. Proc. Natl Acad. Sci. USA 109, 6904–6909 (2012)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Kondoh, H. et al. Glycolytic enzymes can modulate cellular life span. Cancer Res. 65, 177–185 (2005)

    CAS  PubMed  Google Scholar 

  19. 19

    Mazurek, S. Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells. Int. J. Biochem. Cell Biol. 43, 969–980 (2011)

    CAS  Article  Google Scholar 

  20. 20

    Chaneton, B. et al. Serine is a natural ligand and allosteric activator of pyruvate kinase. Nature 491, 458–462 (2012)

    ADS  CAS  Article  Google Scholar 

  21. 21

    Okamura, S. et al. Identification of seven genes regulated by wild-type p53 in a colon cancer cell line carrying a well-controlled wild-type p53 expression system. Oncol. Res. 11, 281–285 (1999)

    CAS  PubMed  Google Scholar 

  22. 22

    Stambolsky, P. et al. Regulation of AIF expression by p53. Cell Death Differ. 13, 2140–2149 (2006)

    CAS  Article  Google Scholar 

  23. 23

    Linke, S. P. et al. A reversible, p53-dependent G0/G1 cell cycle arrest induced by ribonucleotide depletion in the absence of detectable DNA damage. Genes Dev. 10, 934–947 (1996)

    CAS  Article  Google Scholar 

  24. 24

    Messina, E. et al. Guanine nucleotide depletion triggers cell cycle arrest and apoptosis in human neuroblastoma cell lines. Int. J. Cancer 108, 812–817 (2004)

    CAS  Article  Google Scholar 

  25. 25

    Deng, C. et al. Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 82, 675–684 (1995)

    CAS  Article  Google Scholar 

  26. 26

    Almasan, A. et al. Deficiency of retinoblastoma protein leads to inappropriate S-phase entry, activation of E2F-responsive genes, and apoptosis. Proc. Natl Acad. Sci. USA 92, 5436–5440 (1995)

    ADS  CAS  Article  Google Scholar 

  27. 27

    Dimri, G. P. et al. Inhibition of E2F activity by the cyclin-dependent protein kinase inhibitor p21 in cells expressing or lacking a functional retinoblastoma protein. Mol. Cell. Biol. 16, 2987–2997 (1996)

    CAS  Article  Google Scholar 

  28. 28

    Grüning, N.-M. & Ralser, M. Cancer: sacrifice for survival. Nature 480, 190–191 (2011)

    ADS  Article  Google Scholar 

  29. 29

    Anastasiou, D. et al. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 334, 1278–1283 (2011)

    ADS  CAS  Article  Google Scholar 

  30. 30

    Kalhan, S. C. & Hanson, R. W. Resurgence of serine: an often neglected but indispensable amino acid. J. Biol. Chem. 287, 19786–19791 (2012)

    CAS  Article  Google Scholar 

  31. 31

    Bunz, F. et al. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282, 1497–1501 (1998)

    CAS  Article  Google Scholar 

  32. 32

    Donehower, L. A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215–221 (1992)

    ADS  CAS  Article  Google Scholar 

  33. 33

    Vigneron, A. M., Ludwig, R. L. & Vousden, K. H. Cytoplasmic ASPP1 inhibits apoptosis through the control of YAP. Genes Dev. 24, 2430–2439 (2010)

    CAS  Article  Google Scholar 

Download references

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.

Corresponding author

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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