The role of amino acids in cancer metabolism

By Hung-Hsi (Chelsea) Chen

Serine is a non-essential amino acid derived from glycine. In healthy individuals, serine is important for the proper function of the brain, especially the central nervous system (CNS), production of nucleotides, muscle formation, immune system and fatty acid metabolism. However, a vital amino acid such as serine can also contribute to health issues when it comes to cancer metabolism. 

The serine synthesis pathway (SSP) has been found to be dysregulated in cancer. In healthy, nondividing cells, metabolism aims to maintain homeostasis by fueling day to day processes that require energy in the form of ATP by oxidizing nutrients that are available. On the other hand, dividing cells require amino acids for protein synthesis, production of sphingolipids for membrane synthesis and nucleotides for DNA replication. The precursors of all macromolecules required in dividing cells are derived from carbon and nitrogen (Newman et al., 2017) 

Serine gets converted to glycine by an enzyme called hydroxymethyltransferase (SHMT). This process gives out one additional carbon to tetrahydrofolate, producing CH₂-THF to be made into thymidine for purine synthesis. Additionally, as a folate precursor, CH₂-THF aids in the formation of S-adenosylmethionine, which is an important methyl donor in methylation reactions that regulate genetic and epigenetic expression. Due to its versatile use, serine metabolism and its availability is crucial for cancer cell proliferation (Mattaini et al., 2016).

Serine can either be supplied to cells extracellularly, or it can be synthesized from glucose intracellularly. It has been found that SSP is the pathway responsible for intracellular serine synthesis with the help from phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase and phosphoserine phosphatase (Mattaini et al., 2016). 

In cancer cells, PHGDH expression is higher compare to normal cells, and the fastest growing ones had higher PHGDH activity (Davis et al., 1970). PHGDH protein expressions is transcriptionally activated by upregulating transcription factor 4 and c-Myc. A few subtypes of cancer have been associated with increased PHGDH expression, specifically ones that have shorter survival time and time to relapse, as well as higher tumour grade, with the triple-negative breast cancer as one of them. 

The relationship between PHGDH and cancer proliferation allows us to find a potential target for future therapy. PHGDH is needed to support cancer cell proliferation and growth, hence, in theory, inhibiting it would prevent the cancer growth. Unfortunately, although inhibiting PHGDH may seem as an ideal therapy to inhibit tumour proliferation, low PHGDH expression may cause harmful effects on the brain (Mullarky et al., 2016). In mice, PHGDH deletion led to embryonic lethality due to faults in development affecting the CNS. Therefore, future potential therapies should aim towards developing inhibitors that are unable to cross the blood brain barrier to stop neurological complications (Mattaini et al., 2016).

Recent studies explored the relationship between serine and glycine. In a study done by Lasbuschagne et al. in 2014, their results suggest that cells prefer serine uptake and glycine excretion in the abundance of serine (Labuschagne et al., 20-14). In contrast, they only take up glycine when serine is not present. Cells prefer serine over glycine because the conversion from the former to the latter gives off one carbon for synthesizing nucleotides for DNA replication. Nucleotide biosynthesis is regulated by p53, a tumour suppressor protein. Mice with cells with p53^+/+ adjusted to low levels of serine by undergoing cell cycle arrest. In contrast, p53^-/- cells continued synthesizing nucleotide even with low serine availability.  

Pyruvate kinase, an enzyme involved in the last step of glycolysis, has multiple isoforms, with its M2 isoform selected for in cancer. PKM2’s activity is inversely correlated with the cell’s SSP activity. PKM2 activity decreases upon a decrease intracellular serine levels, which allows for glucose carbon influx into the SSP to make up for the decrease in serine levels. Cancer’s ability to decrease PKM2 activity has been proven to be beneficial for their survival. A decrease in PKM2 activity is reduces the cell’s demand for oxygen, which could be beneficial when the cell is under hypoxic conditions.  

In conclusion, cell proliferation in cancer is shown to be limited in the absence of serine. This is important for not only developing potential anti-tumour therapies, but also to complement the patient’s treatment by providing them with serine-free diets. Further studies are required to find out how PHGDH activity can be limited without harming the brain metabolism of the patient.

References:

Davis, J.L., Fallon, H.J. & Morris, H.P. 1970, “Two enzymes of serine metabolism in rat liver and hepatomas”, Cancer research (Chicago, Ill.), vol. 30, no. 12, pp. 2917.

Labuschagne, C.F., van den Broek, Niels J. F, Mackay, G.M., Vousden, K.H. & Maddocks, O.D.K. 2014, “Serine, but Not Glycine, Supports One-Carbon Metabolism and Proliferation of Cancer Cells”, Cell reports (Cambridge), vol. 7, no. 4, pp. 1248-1258.

Mattaini, K.R., Sullivan, M.R. & Vander Heiden, M.,G. 2016, “The importance of serine metabolism in cancer”, The Journal of cell biology, vol. 214, no. 3, pp. 249-257.

Mullarky, E., Lucki, N.C., Reza, B.Z., Anglin, J.L., Gomes, A.P., Nicolay, B.N., Jenny, C.Y.W., Christen, S., Takahashi, H., Singh, P.K., Blenis, J., David Warren, J., Sarah-Maria Fendt, Asara, J.M., DeNicola, G.M., Lyssiotis, C.A., Lairson, L.L. & Cantley, L.C. 2016, “Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers”, Proceedings of the National Academy of Sciences – PNAS, vol. 113, no. 7, pp. 1778-1783.

Newman, A.C. & Maddocks, O.D.K. 2017, “Serine and Functional Metabolites in Cancer”, Trends in cell biology, vol. 27, no. 9, pp. 645-657.