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

Cancer cells in culture are often grown in media conditions containing unphysiological metabolite levels. Here, the authors grow cells under physiological metabolite levels to further understand the reliance of cells on serine and find that when grown under these conditions the cells are less sensitive to serine withdrawal. 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.

Automated summary

Cancer cells grown under physiological metabolite levels show decreased sensitivity to serine withdrawal. Limiting serine availability leads to increased de novo serine synthesis and utilization of hypoxanthine to support purine synthesis. This study enhances our understanding of serine metabolism under physiologically relevant nutrient conditions and suggests potential interventions for enhancing therapeutic response to dietary serine/glycine limitation.