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Serine and one-carbon metabolism in cancer

Key Points

  • 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.

Abstract

The non-essential amino acid serine supports several metabolic processes that are crucial for the growth and survival of proliferating cells, including protein, amino acid and glutathione synthesis. As an important one-carbon donor to the folate cycle, serine contributes to nucleotide synthesis, methylation reactions and the generation of NADPH for antioxidant defence. Many cancer cells are highly dependent on serine, a trait that provides several novel therapeutic opportunities, either through the inhibition of de novo serine synthesis or by limiting the availability or uptake of exogenous serine.

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Figure 1: The serine synthesis pathway.
Figure 2: Overview of serine metabolism.
Figure 3: Serine and the folate cycle.
Figure 4: Intersection of metabolic pathways to support nucleotide production and antioxidant defence.
Figure 5: The methionine cycle.
Figure 6: Regulation of serine metabolism genes in cancer.

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Acknowledgements

We would like to thank O. Maddocks and C. Labuschagne for helpful comments on the manuscript. This work was supported by Cancer Research UK grant C596/A10419 and European Research Council Grant 322842-METABOp53. We apologize to authors of studies that have contributed to this field but that we have been unable to cite owing to space constraints.

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Correspondence to Karen H. Vousden.

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K.H.V. is on the Science Advisory Board of Raze Therapeutics.

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Glossary

Non-essential amino acids

(NEAAs). Amino acids that can be synthesized de novo by the cell, and therefore need not be provided through an exogenous source, such as diet. These are alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine and tyrosine. However, several of these become conditionally essential under certain conditions.

Gluconeogenesis

Metabolic pathway for the generation of glucose from non-carbohydrate sources such as pyruvate, lactate or amino acids — essentially the reverse of glycolysis.

Auxotrophic

Dependence on a nutrient for growth.

One-carbon metabolism

The pathways that allow for the transfer of single carbon units through folate intermediates for use in purine and thymidylate synthesis, NADP+/NADPH production and methylation reactions. Although serine and glycine are major sources of one-carbon units, several other one-carbon donors are used by the cell, including choline, which is converted into betaine to provide one-carbon units in the remethylation of homocysteine to methionine. The dimethylglycine produced through this reaction can act as a further one-carbon source for the mitochondrial folate cycle.

Pentose phosphate pathway

(PPP). An alternative pathway of glucose metabolism that produces NADPH for reductive biosynthesis and ribose 5-phosphate for nucleotide synthesis.

Oxidative phosphorylation

Mitochondrial metabolic process that involves the transfer of electrons from NADH or FADH2 through the electron transport chain to reduce molecular oxygen to water. The energy released is used to regenerate ATP from ADP.

Reactive oxygen species

(ROS). Reactive molecules derived from oxygen that can modulate the activity of redox-sensitive proteins or cause damage to nucleic acids, proteins and lipids.

Oncometabolite

A metabolite whose abnormal accumulation is associated with cancer development.

Glutaminolysis

Metabolic pathway of glutamine metabolism, allowing the use of carbon and nitrogen from glutamine to provide energy and anabolic intermediates.

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Yang, M., Vousden, K. Serine and one-carbon metabolism in cancer. Nat Rev Cancer 16, 650–662 (2016). https://doi.org/10.1038/nrc.2016.81

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