Abstract
The glutaminolysis and serine–glycine–one-carbon pathways represent metabolic reactions that are reprogramed and upregulated in cancer; these pathways are involved in supporting the growth and proliferation of cancer cells. Glutaminolysis participates in the production of lactate, an oncometabolite, and also in anabolic reactions leading to the synthesis of fatty acids and cholesterol. The serine–glycine–one-carbon pathway is involved in the synthesis of purines and pyrimidines and the control of the epigenetic signature (DNA methylation, histone methylation) in cancer cells. Methionine is obligatory for most of the methyl-transfer reactions in the form of S-adenosylmethionine; here, too, the serine–glycine–one-carbon pathway is necessary for the resynthesis of methionine following the methyl-transfer reaction. Glutamine, serine, glycine, and methionine are obligatory to fuel these metabolic pathways. The first three amino acids can be synthesized endogenously to some extent, but the need for these amino acids in cancer cells is so high that they also have to be acquired from extracellular sources. Methionine is an essential amino acid, thus making it necessary for cancer cells to acquire this amino acid solely from the extracellular milieu. Cancer cells upregulate specific amino acid transporters to meet this increased demand for these four amino acids. SLC6A14 and SLC38A5 are the two transporters that are upregulated in a variety of cancers to mediate the influx of glutamine, serine, glycine, and methionine into cancer cells. SLC6A14 is a Na+/Cl− -coupled transporter for multiple amino acids, including these four amino acids. In contrast, SLC38A5 is a Na+-coupled transporter with rather restricted specificity towards glutamine, serine, glycine, and methionine. Both transporters exhibit unique functional features that are ideal for the rapid proliferation of cancer cells. As such, these two amino acid transporters play a critical role in promoting the survival and growth of cancer cells and hence represent novel, hitherto largely unexplored, targets for cancer therapy.
Highlights
Introduction iationsCancer cells have been shown to hijack specific metabolic pathways that occur in normal cells and reprogram them to meet the increased demands for various nutrients and metabolites in support of their rapid proliferation
We focus on cancer-cell-specific pathways associated with glucose and amino acid metabolism, with a special emphasis on the amino acids glutamine, serine, glycine, and methionine and the two amino acid transporters SLC6A14 and SLC38A5 that supply the cancer cells with these amino acids
Glutaminolysis is a pathway in which the carbon skeleton of glutamine is used to produce lactic acid in cancer cells; this is in some ways similar to aerobic glycolysis, where the carbon skeleton in glucose is used to produce lactic acid
Summary
Cancer cells must acquire certain specific biochemical and cell-biological features to ensure their characteristic sustained rapid growth and proliferation. This includes, but is not limited to, the anabolic capacity to synthesize lipids (phospholipids, cholesterol) necessary for membrane biogenesis, and macromolecules (nucleic acids, proteins) necessary for cell division, robust antioxidant machinery to prevent detrimental effects of oxidative stress, fine-tuning of regulatory pathways to balance the biological needs and potential deleterious effects of excess in case of specific nutrients (e.g., iron), generation of specific metabolites with unique functions suitable to sustain cell survival (oncometabolites), and appropriate changes in epigenetic control of gene transcription to promote the proteomic/enzymatic profile optimal for rapid growth with simultaneous suppression of senescence and cell death Cancer cells achieve these features by judiciously reprogramming metabolic pathways via suppression, activation, or modification of specific biochemical reactions. These pathways do occur in normal cells depending on specific biologic conditions of the cells; cancer cells hijack these pathways and reprogram them to best suit their needs
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