Cancer cells show increased consumption of and dependence on glutamine.
Glutamine metabolism fuels the tricarboxylic acid (TCA) cycle, nucleotide and fatty acid biosynthesis, and redox balance in cancer cells.
Glutamine activates mTOR signalling, suppresses endoplasmic reticulum stress and promotes protein synthesis.
Cancer cells may metabolize glutamate to α-ketoglutarate through one of two different pathways (glutamate dehydrogenase or aminotransferases), with aminotransferases potentially supporting a more biosynthetic and pro-growth phenotype.
Activation of oncogenic pathways and loss of tumour suppressors reprogramme glutamine metabolism in a tissue-dependent manner.
Targeting glutamine metabolism shows promise as an anticancer therapy. Compensatory glutamine metabolism induced by cancer therapies suggests that targeting glutamine metabolism may be used in combination therapy.
The resurgence of research into cancer metabolism has recently broadened interests beyond glucose and the Warburg effect to other nutrients, including glutamine. Because oncogenic alterations of metabolism render cancer cells addicted to nutrients, pathways involved in glycolysis or glutaminolysis could be exploited for therapeutic purposes. In this Review, we provide an updated overview of glutamine metabolism and its involvement in tumorigenesis in vitro and in vivo, and explore the recent potential applications of basic science discoveries in the clinical setting.
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The authors thank R. DeBerardinis (Children's Research Institute at University of Texas Southwestern, Dallas, USA) and J. Coloff (Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA) for helpful commentary and discussion. They apologize to any authors whose work could not be included owing to space limitations. This work is partially supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) (R01CA057341 (C.V.D)), The Leukemia and Lymphoma Society LLS 6106-14 (C.V.D.) and the Abramson Family Cancer Research Institute. B.J.A. and Z.E.S. were supported by the NCI (F32CA180370 and F32CA174148, respectively).
The authors declare no competing financial interests.
A type of endocytosis in which extracellular fluid and nutrients are engulfed and taken up into vesicles called macropinosomes. The contents can then be digested by lysosomal degradation to provide nutrients for metabolism.
Refers to macroautophagy, which is a process of bulk cytoplasmic and organelle degradation by specialized organelles called autophagosomes, which then deliver the contents to the lysosome. Autophagy is increased under many forms of stress and can provide nutrients for metabolism.
A class of enzymes, also known as transaminases, that catalyse the reaction between an α-keto acid such as pyruvate and an α-amino acid to form a different amino acid and α-keto acid. For example, glutamate–pyruvate transaminase (GPT, also known as alanine aminotransferase) transfers a nitrogen from glutamate to pyruvate to make alanine and α-ketoglutarate.
The genetic or epigenetic alterations (to activate an oncoprotein or disable a tumour suppressor pathway) that drive the evolution and phenotype of a given tumour.
- Caloric restriction
Restricting the available calories to a model organism, such as a mouse or Caenorhabditis elegans, without undernourishing them. Caloric restriction has been shown in several species to delay age-associated diseases and dramatically extend lifespan.
- One-carbon metabolism pathway
A pathway centred on the metabolism of folate, an important carbon donor for DNA methylation and purine nucleotide synthesis. This pathway is linked to the de novo biosynthesis pathways of serine and glycine.
- Reductive carboxylation
A process that occurs in some normal and cancer cells whereby α-ketoglutarate proceeds 'backwards' through the tricarboxylic acid cycle, being reduced through the consumption of NADPH by isocitrate dehydrogenase in the non-canonical reverse reaction to form citrate. This citrate may then be used in fatty acid synthesis.
- Integrated stress response
(ISR). A stress response pathway that responds to various cellular insults, including amino acid deprivation, through the GCN2 kinase, to phosphorylate eukaryotic translation initiation factor 2α (eIF2α), halt general cap-dependent protein translation and increase transcription of endoplasmic reticulum chaperone proteins. The ISR may eventually result in apoptotic cell death if the stress is not resolved.
- Endoplasmic reticulum (ER) stress
Refers to various stresses that lead to protein misfolding and activate the unfolded protein response (UPR). The UPR, which shares molecular machinery with the integrated stress response, halts cap-dependent translation, induces expression of ER chaperone proteins and can lead to death if the stress is not resolved.
- Cap-dependent translation
In most eukaryotic mRNAs, translation relies on eukaryotic translation initiation factor 4E (eIF4E) binding to the 5′ mRNA cap (a modified nucleotide), along with the ribosome and other initiation factors. Certain stress pathways including endoplasmic reticulum stress and the integrated stress response inhibit cap-dependent translation through inhibitory phosphorylation of the initiation factor eIF2α.
A nitrogenous sugar created from a monosaccharide and amino acids that can be used to modify proteins to aid in protein folding and trafficking.
- Electron transport chain
A series of transmembrane protein complexes, present on the inner membrane of mitochondria, that transfer electrons via redox reactions to the terminal electron acceptor oxygen, which is reduced with binding of protons to a water molecule. This generates a proton gradient that powers ATP synthase to produce ATP. Premature leakage of electrons to oxygen can lead to production of reactive oxygen species.
A tripeptide (glutamate–cysteine–glycine) that acts as an important antioxidant. The reduced form (GSH) can react with H2O2 to form the oxidized form (GSSG).
(2HG). An α-hydroxy acid sometimes produced at high levels by cancer cells, which structurally resembles α-ketoglutarate and so inhibits α-ketoglutarate-dependent enzymes such as the Jumonji-family histone demethylases. The D-2HG enantiomer is produced downstream of mutant isocitrate dehydrogenase enzymes in glioma and acute myelogenous leukaemia, and the L-2HG enantiomer is produced under hypoxia.
- Synthetic lethality
An effect in which two inhibitors or losses of function that, individually, do not produce death in cancer cells, if combined, synergistically induce death. Given that cancers may alter their metabolism in response to traditional chemotherapy and targeted agents, metabolic inhibitors such as inhibitors of glutamine metabolism are particularly attractive targets in synthetic lethality studies.
- Epithelial-to-mesenchymal transition
(EMT). A complex process observed in invasive solid tumours of epithelial origin in which the cancer cells acquire a mesenchymal phenotype, break through the basement membrane and enter the bloodstream or lymphatic system by the process of intravasation. EMT is promoted by many genetic, epigenetic and physiological alterations commonly found in cancer.
An intracellular iron-dependent form of cell death that is distinct from apoptosis.
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Altman, B., Stine, Z. & Dang, C. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer 16, 619–634 (2016). https://doi.org/10.1038/nrc.2016.71
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