Cancer specific non-essential amino acid metabolism – a role for targeted dietary intervention in cancer therapy?
Oliver D. K . Maddocks1,2, Dimitris Athineos1 , Eric C. Cheung1, Pearl Lee1, Tong Zhang2, Julianna Blagih1, Kirsteen Campbell1, Niels van den Broek1, Gillian M. Mackay1, Christiaan F. Labuschagne1, Fatih Ceteci1,3, Owen J. Sansom1, Karen Blyth1 and Karen H. Vousden1
1 Cancer Research UK Beatson Institute, Switchback Road, Glasgow, G61 1BD, UK
2 University of Glasgow Institute of Cancer Sciences, Switchback Road, Glasgow, G61 1QH,
3 Institute for Tumour Biology and Experimental Therapy, Georg-Speyer-Haus, Paul-Ehrlich-
Strasse 42-44, 60596 Frankfurt am Main, Germany
Altered cell metabolism is a fundamental hallmark of cancer and tumour cells acquire a range of metabolic perturbations and adaptations that support proliferation and survival. To sustain enhanced growth, cancer cells become dependent on uptake of nutrients such as glucose and amino acids. We have undertaken extensive studies to characterise the dependency of cancer cells on the non-essential amino acids serine and glycine; including the metabolic pathways dependent on these nutrients, and how this phenotype can be exploited for improved cancer therapy.
To elucidate metabolic pathways involved in serine and glycine metabolism we have utilised and developed steady state metabolomics and carbon-13 labelled metabolic flux assays. These approaches, combined with conventional protein expression analysis and functional assays, have allowed us to characterise serine and glycine metabolism in cancer cells in vitro and in vivo.
We have found that many cancer cell lines are sensitive to serine starvation, despite the ability of these cells to synthesise serine de novo. Cancer cells undergo extensive metabolic remodelling in response to serine starvation requiring a balance between nucleotide and glutathione synthesis aided by the tumour suppressor p53. We have also characterised why excess glycine (a direct metabolite of serine) can inhibit cell proliferation when given in excess. In exploring the metabolic links between the methionine cycle and serine
dependent one-carbon metabolism we have found that cancer cells do not ordinarily use serine to re-synthesise methionine, but rather use serine to support the methionine cycle – and DNA & RNA methylation – via de novo ATP synthesis. In pre-clinical studies with a range of murine models we show that certain tumours are sensitive to dietary serine restriction, which significantly improves survival as a sole therapeutic intervention.
This work establishes a strong foundation for the continued investigation of dietary non-essential amino acid restriction as an adjunct to conventional chemo/radiotherapy.