It has been found that cancerous cells follow metabolic remodeling to sustain cell growth and proliferation. Cancer cells require a large amount of energy as well as building blocks to synthesize new biomolecules like nucleic acids, proteins, and lipids required for cell proliferation and cofactors that involve in the maintenance of cellular redox reactions.
Glucose and glutamine play an important role in providing the source of intermediates in the metabolic pathways such as glycolysis and the TCA cycle while serine and glycine are actively involved in the anabolic pathways.
Biosynthesis of serine is a critical point in glucose conversion. Either from dietary source or from the glycolytic pathway, obtained serine is converted into glycine, which is then used to provide the carbon units for one-carbon metabolism. One-carbon metabolism is a complex metabolic process that involves folate-based reactions. It is required for the synthesis of proteins, lipids, nucleic acids and most of the cofactors.
Glycolysis not only provides ATP and energy in most of the cells, but it is also used in anabolic pathways in the cancer cells for tumor growth. The 3-phosphoglycerate is a key intermediate of glycolysis that diverts the glycolytic pathway to the serine biosynthesis in the cancer cells. Serine biosynthesis involves three reactions. About 10% of the 3-phosphoglycerate from the glycolysis is oxidized to the serine precursor 3-phosphohydropyruvate catalyzed by NAD-dependent Phosphoglycerate Dehydrogenase (PHGDH).
In the next two successive steps, 3-phosphohydropyruvate is converted into the serine. 3-phosphohydropyruvate is first converted to 3-Phosphorserine catalyzed by Phosphoserine Aminotransferase-1 (PSAT1) and then, 3-Phosphoserine is converted to serine catalyzed by Phosphoserine Phosphatase. It is found that the enzyme Phosphoglycerate Dehydrogenase (PHGDH) expression is upregulated in breast cancer and in the melanoma while it is also found that the gene encoding the enzyme is frequently amplified even if there is no oncogene present.
These studies suggest that tumors with amplified PHGDH use serine biosynthesis actively while PHGDH is found to be suppressed in cell lines with elevated PHGDH expression, but not in those cell lines where PHGDH is not elevated. This causes a decrease in cell proliferation with reduced serine biosynthesis. Therefore, to sustain the cancerous growth of the cell and oncogene transformation, PHGDH upregulation and serine biosynthesis are extremely necessary.
Phosphoserine Aminotransferase-1 uses 3-phosphohydropyruvate, a product of PHGDH to convert glutamate to α-ketoglutarate. α-ketoglutarate is an intermediate of the TCA cycle that refuels the TCA cycle to sustain the cancerous cell. In this way, serine biosynthesis acts as a major contributor of the TCA intermediates and is responsible for 50% of the anaplerotic flux to the TCA cycle.
Glycine biosynthesis and p53
Serine biosynthesis not only provides the precursor of the TCA cycle but also provides precursors for other biosynthetic pathways. Serine provides a precursor for the glycine biosynthesis in which serine is converted to glycine catalyzed by Serine Hydroxymethyltransferase (SHMT). Glycine is an important source of methyl groups for the one-carbon pools required for the biosynthesis of different biomolecules, including glutathione, protein, and purine nucleotides.
P53 is a tumor suppressor protein that acts as a mediator of various cellular responses. It also helps the cancer cells to deal with serine deficiency and oxidative stress. It also preserves the antioxidant capacity of the cell. It is found that cells lacking the p53 do not respond to the serine starvation caused by oxidative stress and leads to severely impaired proliferation.
During the serine starvation, the p53-p21 axis is activated which leads to the cell cycle arrest promoting the cell survival and depleting the stored serine to glutathione synthesis to counteract the reactive oxygen species formation.
Recently, it has also been found that p73, a member of p53, plays an important role in the serine biosynthesis and supports the cancer cell under metabolic stress. TAp73, a downstream signaling molecule of p73 activates the serine biosynthesis leading to the increases in the intracellular levels of the serine, glycine, and glutathione while Tap73 depletion lowers the cancer cell proliferation during the serine and glycine starvation.
All these reveal how serine is important for the cancer cell metabolism, and therefore, cancer cells show sensitivity to the serine depletion. And serine depletion may be utilized as a therapeutic strategy for the treatment of human cancer.
One carbon metabolism
In one-carbon metabolism, the folate cycle is coupled with the methionine cycle forming a bicyclic pathway. In this bicycle pathway, folate is reduced to tetrahydrofolate (THF) in a series of enzyme-catalyzed reactions. Thus formed THF involves in different metabolic reactions
Glycine Dehydrogenase catalyzes the cleavage of glycine to release ammonia, carbon dioxide, and a carbon unit of glycine is transferred to the tetrahydrofolate to form methyl-THM through the folate cycle. Methyl-THF donates a one-carbon unit to homocysteine forming methionine through the methionine cycle.
One carbon metabolism provides a one-carbon unit for the synthesis of different intermediates essential to the synthesis of proteins, lipids, and nucleic acids. And all these macromolecules are required for cellular growth and proliferation. Synthesis of dTMP by the methylation of dUMP requires methyl-THF while purine synthesis requires 10-formyl-THF and 5,10-methylene-THF. Similarly, methionine provides a one-carbon unit to the phosphatidylcholine synthesis, which contributes half of the membrane lipids and to the protein synthesis, histone methylation, and DNA methylation in the form of S-adenosylmethionine (SAM).
Glycine and one-carbon metabolism also play a role in the cellular redox balance. The reduction of THF to folic acid catalyzed by THF reductase requires one molecule of NADPH per turn and thus maintains the NADP+/NADPH ratio. Glutathione formed from glycine, cysteine, and glutamate also involves in the maintenance of the NADP+/NADPH ratio.
Glycine can also be directed to the purine nucleotide biosynthesis where it provides two carbon units and a nitrogen unit in the purine ring. It is also used in the glutathione biosynthesis maintaining the cellular redox balance and in then mitochondrial glycine is used to synthesize heme a prosthetic group of the hemoglobin.
In a recent study, it has been found that glycine and its catabolism promote tumorigenesis and malignancy suggesting that glycine metabolism can be a new way to target cancer therapy. In this study, researchers analyzed the glycine consumption and mitochondrial glycine biosynthesis where they correlated with the rate of cancer cell proliferation. The results reveal a key role of mitochondria to support the rapid proliferation of cancer cells.
Use of antimetabolites (antifolates) in cancer therapy
The use of the antimetabolites (antifolates) as a drug to treat cancer is a landmark of cancer therapy. Antimetabolites like Methotrexate and Pemetrexed quench the effect of metabolites on the cellular processes. Methotrexate and Pemetrexed are cancer therapy agents currently used to treat a wide range of cancers, including lymphoblastic leukemia, bladder cancer, breast cancer, etc.
They have the ability to inhibit the human Serine Hydroxymethyltransferase (SHMT) thereby inhibiting the mitochondrial glycine biosynthesis. These antifolates also inhibit the Thymidylate synthase and Dihydrofolate reductase.
Other antimetabolites include pralatrexate and 5-fluorouracil. 5-fluorouracil mimics the uracil and inhibits the Thymidylate Synthase leading to the impairment of the dTMP formation and folate cycle disruption. 5-fluorouracil can also be converted intracellularly into 5-fluorouridine which is incorporated into the rRNA molecule and prevents the rRNA processing.
Understanding the metabolic pathways of glycine, serine, and one-carbon metabolism has provided an insight into the metabolism of cancer cells and is considered as drivers of oncogenesis. Therefore, it is necessary to carry out a biochemical dissection of how these metabolic pathways contribute to cancer biology to develop therapeutic potentials.
It is also of great importance to investigate the contribution of serine, glycine, and one-carbon metabolism biosynthesis to the early stage of the tumorigenesis that will help us understand whether these pathways affect the cancer onset or only to the cancer progression and metastasis. Elucidating these aspects will also provide alternative clinical strategies and enable us to design personalized therapy for cancer patients.
Reference: Trends in Biochemical Sciences
Article DOI: dx.doi.org/10.1016/j.tibs.2014.02.004