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.
Highlights
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
We examined three cancer cell lines from different cancer types, A549, HCT116 and MDA-MB-231, whose proliferation is highly dependent on exogenous serine and glycine when grown in DMEM (Fig. 1A)[3,4]
Increasing the serine levels in Plasmax to 400 μM did not change the expression of activating transcription factor-4 (ATF-4) or phosphoglycerate dehydrogenase (PHGDH) (Supplementary Fig. 2F). These results indicated that the superphysiological levels of amino acids such as arginine in DMEM suppress a level of ATF-4 activity that is seen under more physiological concentrations of these amino acids, which is in line with upregulation of the ATF-4 pathway in human and mouse tumour compared to normal tissue[31]
Summary
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. 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. Most of the in vitro studies examining responses to nutrient deprivation have been carried out using classical cell culture media, which were formulated half a century ago with the aim of deriving and maintaining mouse or human cell lines in culture[11] These formulations did not attempt to recapitulate the human metabolic environment and lack some metabolites present in human circulation while containing an over-abundance of others[12]. We observe that cells grown in Plasmax are less sensitive to serine/ glycine deprivation due to a multi-layer rewiring of serine metabolism in these more physiologically relevant conditions
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