Trends in Cancer
Volume 3, Issue 3, March 2017, Pages 169-180
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Opinion
Glutamine Metabolism in Cancer: Understanding the Heterogeneity

https://doi.org/10.1016/j.trecan.2017.01.005Get rights and content

Trends

The role of glutamine in cancer metabolism is more complex than previously appreciated.

Glutaminase inhibition effectiveness in vivo is highly dependent on tumor cell origin and tumor microenvironment.

Animal studies and anchorage-independent cell culture studies can greatly complement monolayer cell culture studies and may reveal unique metabolic patterns.

The synthesis or uptake, and the utilization, of glutamine in cancer cells is highly flexible and is dependent on cell origin, oncogenic drivers, and the tumor microenvironment.

Some tumor types rely on catabolism of exogenous glutamine, and might be effectively targeted by therapeutic regimes involving glutaminase inhibition.

Different metabolic pathways, including glutamine catabolism, can achieve TCA cycle anaplerosis.

Reliance on glutamine has long been considered to be a hallmark of cancer cell metabolism. However, some recent studies have challenged this notion in vivo, prompting a need for further clarification of the role of glutamine metabolism in cancer. We find that there is ample evidence of an essential role for glutamine in tumors, and that a variety of factors, including tissue type, the underlying cancer genetics, the tumor microenvironment, and other variables such as diet and host physiology collectively influence the role of glutamine in cancer. Thus the requirements for glutamine in cancer are overall highly heterogeneous. In this review we discuss the implications both for basic science and for targeting glutamine metabolism in cancer therapy.

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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