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The impact of physiological metabolite levels on serine uptake, synthesis and utilization in cancer cells

Author

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  • Marc Hennequart

    (The Francis Crick Institute)

  • Christiaan F. Labuschagne

    (The Francis Crick Institute)

  • Mylène Tajan

    (The Francis Crick Institute)

  • Steven E. Pilley

    (The Francis Crick Institute)

  • Eric C. Cheung

    (The Francis Crick Institute)

  • Nathalie M. Legrave

    (The Francis Crick Institute)

  • Paul C. Driscoll

    (The Francis Crick Institute)

  • Karen H. Vousden

    (The Francis Crick Institute)

Abstract

Serine is a non-essential amino acid that is critical for tumour proliferation and depletion of circulating serine results in reduced tumour growth and increased survival in various cancer models. While many cancer cells cultured in a standard tissue culture medium depend on exogenous serine for optimal growth, here we report that these cells are less sensitive to serine/glycine depletion in medium containing physiological levels of metabolites. The lower requirement for exogenous serine under these culture conditions reflects both increased de novo serine synthesis and the use of hypoxanthine (not present in the standard medium) to support purine synthesis. Limiting serine availability leads to increased uptake of extracellular hypoxanthine, sparing available serine for other pathways such as glutathione synthesis. Taken together these results improve our understanding of serine metabolism in physiologically relevant nutrient conditions and allow us to predict interventions that may enhance the therapeutic response to dietary serine/glycine limitation.

Suggested Citation

  • Marc Hennequart & Christiaan F. Labuschagne & Mylène Tajan & Steven E. Pilley & Eric C. Cheung & Nathalie M. Legrave & Paul C. Driscoll & Karen H. Vousden, 2021. "The impact of physiological metabolite levels on serine uptake, synthesis and utilization in cancer cells," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26395-5
    DOI: 10.1038/s41467-021-26395-5
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    as
    1. Mylène Tajan & Marc Hennequart & Eric C. Cheung & Fabio Zani & Andreas K. Hock & Nathalie Legrave & Oliver D. K. Maddocks & Rachel A. Ridgway & Dimitris Athineos & Alejandro Suárez-Bonnet & Robert L. , 2021. "Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    2. Kıvanç Birsoy & Richard Possemato & Franziska K. Lorbeer & Erol C. Bayraktar & Prathapan Thiru & Burcu Yucel & Tim Wang & Walter W. Chen & Clary B. Clish & David M. Sabatini, 2014. "Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides," Nature, Nature, vol. 508(7494), pages 108-112, April.
    3. Richard Possemato & Kevin M. Marks & Yoav D. Shaul & Michael E. Pacold & Dohoon Kim & Kıvanç Birsoy & Shalini Sethumadhavan & Hin-Koon Woo & Hyun G. Jang & Abhishek K. Jha & Walter W. Chen & Francesca, 2011. "Functional genomics reveal that the serine synthesis pathway is essential in breast cancer," Nature, Nature, vol. 476(7360), pages 346-350, August.
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