Key Points
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Cancer-associated expression changes and mutations in metabolic enzymes can alter levels of metabolites.
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The accumulation of certain metabolites can support cancer cell proliferation by increasing flux through anabolic metabolism.
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Competitive inhibition of α-ketoglutarate-dependent dioxygenases by 2-hydroxyglutarate (2HG), succinate and fumarate can promote cancer-associated signalling.
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Reactive metabolites, such as reactive oxygen species, fumarate, methylglyoxal and fumarylacetoacetate can affect cancer phenotypes.
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Fumarylacetoacetate is an oncometabolite in the liver of patients with fumarylacetoacetate hydrolase deficiency.
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Metabolite level alterations in cancer present new opportunities to design novel therapeutics.
Abstract
Altered cell metabolism is a characteristic feature of many cancers. Aside from well-described changes in nutrient consumption and waste excretion, altered cancer cell metabolism also results in changes to intracellular metabolite concentrations. Increased levels of metabolites that result directly from genetic mutations and cancer-associated modifications in protein expression can promote cancer initiation and progression. Changes in the levels of specific metabolites, such as 2-hydroxyglutarate, fumarate, succinate, aspartate and reactive oxygen species, can result in altered cell signalling, enzyme activity and/or metabolic flux. In this Review, we discuss the mechanisms that lead to changes in metabolite concentrations in cancer cells, the consequences of these changes for the cells and how they might be exploited to improve cancer therapy.
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Acknowledgements
This work was supported by a postdoctoral fellowship, PF-15-096-01-TBE from the American Cancer Society to L.B.S., US National Institutes of Health (NIH) (T32 GM007753) to D.Y.G., the Burroughs Wellcome Fund, the Ludwig Center at the Massachusetts Institute of Technology (MIT), and the NIH (P30CA1405141, GG006413 and R01 CA168653) to M.G.V.H.
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M.G.V.H. is a consultant and Scientific Advisory Board (SAB) member for Agios Pharmaceuticals, which seeks to target metabolism for cancer therapy, and is also an SAB member for Aeglea Biotherapeutics.
Glossary
- Catabolic
-
The breakdown of complex molecules into simpler molecules, by which energy is extracted from the breakdown process to produce ATP, reducing equivalents or other intermediates.
- Anabolic
-
The production of complex molecules from simpler molecules, including for the purpose of accumulating biomass. Requires the input of energy to catalyse otherwise unfavourable reactions.
- Oncometabolite
-
A metabolite that, when present at high enough levels, is sufficient to promote the transformation of a cell or to confer a cancer-associated phenotype.
- Steady-state concentrations
-
When the concentrations of metabolites are constant over time. Metabolic perturbations that alter the production and/or consumption rates of metabolites will result in new steady-state concentrations.
- By-products or error products of metabolism
-
Metabolites that are generated as a result of non-enzyme-catalysed reactions or from the promiscuous activity of an enzyme acting on a non-canonical substrate. Typically, these metabolites are not used in support of established catabolic or anabolic metabolic pathways.
- Metabolic flux
-
Indicates the rate of a metabolic reaction or a series of reactions in a pathway. Flux does not necessarily change as a result of enzyme expression or a change in metabolite levels.
- Reductive carboxylation
-
The NADPH-consuming, CO2-fixing reaction that is catalysed by isocitrate dehydrogenase 1 (IDH1) or IDH2 to reduce and carboxylate α-ketoglutarate (α-KG) and produce isocitrate. Although used in this Review to refer to the reductive carboxylation reaction catalysed by IDH, reductive carboxylation of other substrates to produce additional products is also possible.
- α-KG-dependent dioxygenases
-
A family of enzymes that use O2, α-ketoglutarate (α-KG) and another substrate to produce a hydroxylated product, succinate and CO2. This family of enzymes includes the prolyl hydroxylases (PHDs), the TET family of cytosine hydroxymethylases and the Jumonji (JMJ) family of histone demethylases.
- Stereospecific
-
Describes a reaction catalysed by an enzyme that has specificity for a stereoisomer of the substrate and/or product.
- Reactive metabolites
-
Metabolites that are sufficiently reactive to form covalent bonds with other biomolecules under physiological conditions in the absence of enzyme catalysis. These metabolites can be by-products of metabolism, as is the case with reactive oxygen species and methylglyoxal, or can exist as intermediary metabolites of canonical metabolic pathways, as is the case with fumarate and fumarylacetoacetate.
- Michael addition
-
A conjugate addition reaction in which a nucleophile, such as a thiolate anion from glutathione, undergoes a nucleophilic attack on an α,β-unsaturated carbonyl compound.
- Synthetic lethality
-
A condition in which the combination of two genetic mutations and/or chemical inhibitions leads to cell death, whereas each individual effect does not.
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Sullivan, L., Gui, D. & Heiden, M. Altered metabolite levels in cancer: implications for tumour biology and cancer therapy. Nat Rev Cancer 16, 680–693 (2016). https://doi.org/10.1038/nrc.2016.85
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DOI: https://doi.org/10.1038/nrc.2016.85
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