Serine and one-carbon metabolism in cancer

Serine is a non-essential amino acid that can be taken up by the cell or synthesized de novo from glycolytic intermediates through the serine synthesis pathway (SSP). Serine is used for many biosynthetic pathways, including the one-carbon cycle that supports nucleotide synthesis, methylation reactions and antioxidant defence.Although one-carbon metabolism enzymes are expressed in both the mitochondria and cytosol, most cells generate formate in the mitochondria for use in cytosolic nucleotide synthesis. This directionality in the pathway can also provide mitochondrial NADH, NADPH and ATP.Some cancer cells show amplification of the SSP enzymes, and their survival depends on the sustained expression of these enzymes, even under serine-fed conditions. This seems to reflect a requirement for serine synthesis to maintain nucleotide synthesis.Cancer cells without amplification of the SSP tend to depend on exogenous serine for optimal growth. The switch to de novo serine synthesis under serine starvation leads to increased oxidative stress, which must be managed for successful adaptation.Several oncogenes and tumour suppressor genes can regulate the serine synthesis and one-carbon cycle enzymes, with evidence that changes in their expression and activity can contribute to malignant development and progression.Therapeutic approaches are being developed based on limiting exogenous serine or targeting serine synthesis or metabolism enzymes.