Trends in Cancer
OpinionGlutamine Metabolism in Cancer: Understanding the Heterogeneity
Section snippets
Metabolic Reprogramming in Cancer
Cancer cells undergo a reprogramming of metabolism to maintain bioenergetics, redox status, cell signaling, and biosynthesis in what is often a poorly vascularized, nutrient-deprived microenvironment 1, 2, 3, 4. To supply biosynthetic pathways with precursors, the uptake and catabolism (see Glossary) of specific nutrients are upregulated in tumor cells. In particular, the Warburg effect occurs in many human tumors, such that positron emission tomography (PET) using the glucose analog 18
Culture Conditions and Model Systems Influence Glutamine Metabolism
The ability to culture cell lines derived from human tumors has, over the past 60 years, provided researchers with a powerful tool for studying cancer biology. A common characteristic of mammalian cell lines grown in culture, as noted by Harry Eagle in the 1950s [22], is a dependence on an abundant exogenous supply of the NEAA glutamine. After glucose, glutamine is the most rapidly consumed nutrient by many human cancer cell lines grown in culture 23, 24. However, glutamine requirements are
Metabolic Phenotype Varies with Cancer Subtype and Microenvironment
Different mammalian organs exhibit distinct modes of glutamine metabolism. For example, the kidney mediates net glutamine catabolism, generating ammonia for pH homeostasis and supplying carbon for renal gluconeogenesis [31], whereas lung, skeletal muscle, and adipose tissues exhibit net de novo glutamine synthesis via the enzyme glutamine synthetase (GLUL) [32]. Similarly, human tumors show a range of metabolic phenotypes that vary with the tissue of origin, the cancer subtype, and the tumor
The Impact of Oncogenes on Glutamine Metabolism
Tumors that arise in different organs, but from the same genetic lesion, can also have distinct phenotypes for glutamine metabolism. One study demonstrated that MYC-induced liver tumors exhibit elevated glutamine catabolism, with increased GLS expression and suppressed GLUL expression relative to surrounding tissue 15, 34. By contrast, MYC-induced NSCLC tumors exhibit increased expression of GLUL and accumulate glutamine [34]. MYC can regulate the expression of both GLS and GLUL through
Tumor Glutamine Supply
Glutamine can be imported from the microenvironment by the solute carrier (SLC) group of transporters, including members of the SLC1, SLC6, SLC7, SLC36, and SLC38 families. The Na+/amino acid exchanger SLC1A5 and the unidirectional Na+/Cl−/amino acid symporter SLC6A14 are both regulated by MYC and are overexpressed in several cancers [51]. Some tumors such as pancreatic ductal adenocarcinoma (PDAC) are typically poorly vascularized, and consequently do not have an abundant serum supply of
The Metabolic Fate of Glutamate in Cancer
The first step of glutamine catabolism is its conversion to glutamate, which is catalyzed by cytosolic glutamine amidotransferases or by mitochondrial glutaminases. Glutamine-derived glutamate has diverse fates in proliferating cells, including consumption during protein synthesis, supplying nitrogen for transamination reactions, secretion from the cell in exchange for other nutrients, incorporation into the antioxidant tripeptide glutathione, and conversion into α-KG for TCA cycle anaplerosis.
Epigenetics and Signaling
Underlying some of the connections between tumor tissue-of-origin, microenvironment, and metabolic phenotype, is the tumor epigenetic landscape (Box 1). Many epigenetic modifications and processes are regulated by glutamine-derived metabolites including α-KG, which is a cofactor for Jumonji domain-containing histone demethylases [63]. In a variety of xenograft tumors, the poorly vascularized tumor core shows a selective deficiency of glutamine relative to other amino acids, and a corresponding
Targeting Glutamine Metabolism for Cancer Therapy
The diverse roles played by glutamine in proliferating cells, supplying carbon and reduced nitrogen for biosynthetic reactions and redox homeostasis, present opportunities for targeting glutamine metabolism for cancer therapy [67]. Several approaches are conceivable, including depletion of glutamine in blood serum, blockade of cellular glutamine uptake, and inhibition of enzymes involved in glutamine synthesis or catabolism [62]. L-asparaginases, which are routinely used to treat ALL patients,
Concluding Remarks
Our understanding of the roles played by glutamine in cancer is evolving rapidly, and recent work has provided new insights and also has raised several questions. It is now clear that there is a not a single ‘metabolic map’ or ‘metabolic switch’ describing cancer cell metabolism [74], and the fate of glutamine varies with a range of parameters, including the tissue of origin of a cancer, the genetic aberrations which drive it, the tumor microenvironment, and possibly diet and host metabolism.
Acknowledgments
The authors thank Ralph DeBerardinis and members of the laboratories of R.A.C. and J.W.L. for their helpful comments. The authors apologize to any authors whose work could not be included owing to space limitations. Support from the National Institutes of Health, R01CA193256 (J.W.L.), R00CA168997 (J.W.L.), is gratefully acknowledged. A.A.C. is supported by a graduate fellowship from the King Abdullah International Medical Research Center under the Ministry of National Guard Health Affairs.
Glossary
- Anaplerosis
- the process of replenishing metabolic pathway intermediates. For example, carbon that is lost from the tricarboxylic acid (TCA) cycle to supply biosynthetic reactions can be replenished by glutamine-derived α-ketoglutarate (α-KG), glucose-derived oxaloacetate, etc.
- Auxotroph
- an organism that is unable to synthesize a particular compound required for its growth.
- Catabolism
- describes metabolic pathways that breakdown macromolecules into smaller units and release energy. To be contrasted
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