Glutamine and cancer: cell biology, physiology, and clinical opportunities

Abstract

Glutamine is an abundant and versatile nutrient that participates in energy formation, redox homeostasis, macromolecular synthesis, and signaling in cancer cells. These characteristics make glutamine metabolism an appealing target for new clinical strategies to detect, monitor, and treat cancer. Here we review the metabolic functions of glutamine as a super nutrient and the surprising roles of glutamine in supporting the biological hallmarks of malignancy. We also review recent efforts in imaging and therapeutics to exploit tumor cell glutamine dependence, discuss some of the challenges in this arena, and suggest a disease-focused paradigm to deploy these emerging approaches. IntroductionIt has been nearly a century since the discovery that tumors display metabolic activities that distinguish them from differentiated, non-proliferating tissues and presumably contribute to their supraphysiological survival and growth (1). Interest in cancer metabolism was boosted by discoveries that oncogenes and tumor suppressors could regulate nutrient metabolism, and that mutations in some metabolic enzymes participate in the development of malignancy (2, 3). The persistent appeal of cancer metabolism as a line of investigation lies both in its ability to uncover fundamental aspects of malignancy and in the translational potential of exploiting cancer metabolism to improve the way we diagnose, monitor, and treat cancer. Furthermore, an improved understanding of how altered metabolism contributes to cancer has a high potential for synergy with translational efforts. For example, the demonstration that asparagine is a conditionally essential nutrient in rapidly growing cancer cells paved the way for L-asparaginase therapy in leukemia. Additionally, the avidity of some tumors for glucose uptake led to the development of 18 fluoro-2-deoxyglucose imaging by PET; this in turn stimulated hundreds of studies on the biological underpinnings of tumor glucose metabolism.There continue to be large gaps in understanding which metabolic pathways are altered in cancer, whether these alterations benefit the tumor in a substantive way, and how this information could be used in clinical oncology. In this Review, we consider glutamine, a highly versatile nutrient whose metabolism has implications for tumor cell biology, metabolic imaging, and perhaps novel therapeutics.

Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients

“…In addition to glucose, activated B cells need amino acids for synthesis of antibodies and other proteins, as well as nitrogen, for nucleotide synthesis and other processes (Calder, 2006;Grohmann and Bronte, 2010). As the most abundant amino acid in serum, glutamine is a readily available nutrient for most cells, and is involved in providing nitrogen for synthesis of many amino acids (Caro-Maldonado et al, 2014;Hensley et al, 2013). Several genes associated with amino acid transport and biosynthesis are induced under starvation conditions in various cell types, including B cells (Le et al, 2012;Shotwell et al, 1983).…”

Uncovering metabolism in rhabdomyosarcoma

“…Glutamine utilization via glutaminase (glutaminolysis) provides cancer cells with glutamate that, becoming in turn oxaloacetate, may enter the TCA cycle and partially substitutes for glucose (glutamine anapleurosis). [10][11][12][13] In addition to dependency on glutaminolysis, the majority of human cancers, including breast, colon, ovary, lung, and prostate tumors express high levels of fatty acid synthase (FAS), a key metabolic enzyme that is functional to catalyze the synthesis of long chain saturated fatty acids for supporting the increased demand for membrane biogenesis. 14,15 The therapies currently employed to limit tumor expansion mostly utilize cocktails of antineoplastic drugs that interfere with the cell cycle progression; these agents include cell cycle specific drugs like plant alkaloids (etoposide, topotecan) or DNA synthesis inhibitors (5-fluorouracil, methotrexate) and cell cycle non-specific drugs like crosslinking agents (cyclophosphamide, ifosfamide, cisplatin) or intercalating anthracycline antibiotics (doxorubicin, daunorubicin).…”

Glutamine at focus: versatile roles in cancer

“…Glutamate serves as a source of amino groups for NEAA production, particularly aspartate and alanine. This set of reactions transfers amino groups between glutamate and α-ketoacid which is used to synthesize proteins [16]. Moreover, glutamate can enter into mitochondria and be oxidized to α-ketoglutarate (α-KG), reducing NADP + to NADPH or NAD + to NADH and produces a second molecule of NH 4+ .…”

“…Subsequent in vitro and in vivo experiments have suggested that the monitoring of glutaminolysis could be exploited to generate imaging tracer diagnostics to benefit cancer patients [162,163]. Currently, there have been a number of clinical trials in patients using different radioisotopes, like 11 C, 13 N, or 18 F to image glutamine [16]. Moreover, detailed metabolic maps have been extensively studied in many cancer cell types [164].…”

“…This sheds new light on the importance of this nutrient to cell growth, proliferation, malignancy, and stress resistance [16]. For instance, extracellular glutamine can donate carbon and nitrogen to supply anabolic pathways and energy production.…”