One-carbon metabolism in cancer

Abstract

Cells require one-carbon units for nucleotide synthesis, methylation and reductive metabolism, and these pathways support the high proliferative rate of cancer cells. As such, anti-folates, drugs that target one-carbon metabolism, have long been used in the treatment of cancer. Amino acids, such as serine are a major one-carbon source, and cancer cells are particularly susceptible to deprivation of one-carbon units by serine restriction or inhibition of de novo serine synthesis. Recent work has also begun to decipher the specific pathways and sub-cellular compartments that are important for one-carbon metabolism in cancer cells. In this review we summarise the historical understanding of one-carbon metabolism in cancer, describe the recent findings regarding the generation and usage of one-carbon units and explore possible future therapeutics that could exploit the dependency of cancer cells on one-carbon metabolism.

Figure 1

An overview of one-carbon metabolism and the established/future therapeutics that target this pathway. One-carbon metabolic pathways with established chemotherapeutics highlighted in green and possible targets for future interventions highlighted in red. Solid red lines indicate interventions that are currently in development. Dashed lines indicate possible targets that may be subject to further investigation. Enzymes that regulate these pathways are circled. Serine can be obtained from the diet, or synthesised de novo from the glycolytic intermediate, 3-PG by the SSP, of which PHGDH is a key enzyme. Dietary folate is converted by DHFR first to DHF and then to THF, a one-carbon unit acceptor. Serine is catabolised to glycine by SHMT1/2, which yields a one-carbon unit (C₁) that is accepted by THF to form methylene-THF. Methylene-THF can then be converted to formyl-THF via the intermediate methenyl-THF by the action of MTHFD1/2/1L. Formyl-THF donates its one-carbon unit to purine synthesis. Methylene-THF can either donate its one-carbon unit to thymidylate synthesis or be converted by MTHFR to methyl-THF, which supplies one-carbon units for methionine recycling.

Figure 2

The contribution of one-carbon metabolism to methylation. Serine-dependent one-carbon metabolism supports the methionine cycle and methylation reactions via two distinct pathways. Serine catabolism provides one-carbon units (C₁) and glycine, which are both required for de novo ATP synthesised via purine synthesis. ATP synthesised in this way contributes adenosine for the production of SAM from methionine. After participating in a methylation reaction, SAM becomes S-adenosylhomocysteine (SAH) and then homocysteine. Homocysteine can be re-methylated and recycled back to methionine, which requires a one-carbon unit that can also be sourced from serine catabolism to glycine.