Deberardinis, R. J. & Cheng, T. Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29, 313-324

Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9063, USA.
Oncogene (Impact Factor: 8.46). 11/2009; 29(3):313-24. DOI: 10.1038/onc.2009.358
Source: PubMed


Several decades of research have sought to characterize tumor cell metabolism in the hope that tumor-specific activities can be exploited to treat cancer. Having originated from Warburg's seminal observation of aerobic glycolysis in tumor cells, most of this attention has focused on glucose metabolism. However, since the 1950s cancer biologists have also recognized the importance of glutamine (Q) as a tumor nutrient. Glutamine contributes to essentially every core metabolic task of proliferating tumor cells: it participates in bioenergetics, supports cell defenses against oxidative stress and complements glucose metabolism in the production of macromolecules. The interest in glutamine metabolism has been heightened further by the recent findings that c-myc controls glutamine uptake and degradation, and that glutamine itself exerts influence over a number of signaling pathways that contribute to tumor growth. These observations are stimulating a renewed effort to understand the regulation of glutamine metabolism in tumors and to develop strategies to target glutamine metabolism in cancer. In this study we review the protean roles of glutamine in cancer, both in the direct support of tumor growth and in mediating some of the complex effects on whole-body metabolism that are characteristic of tumor progression.

Download full-text


Available from: Ralph J Deberardinis
  • Source
    • "In growing cells, glutamine is converted to the TCA cycle intermediate a-ketoglutarate through the anaplerotic glutamate dehydrogenase pathway. Glutamine is also an essential nitrogen donor in the synthesis of other non-essential amino acids and nucleotides (DeBerardinis and Cheng, 2010). We noticed that activation of glutamine biosynthesis is essential for growth in sugar-feeding animals, suggesting that sugar and glutamine metabolisms are coupled to ensure proper growth rate. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The ChREBP/Mondo-Mlx transcription factors are activated by sugars and are essential for sugar tolerance. They promote the conversion of sugars to lipids, but beyond this, their physiological roles are insufficiently understood. Here, we demonstrate that in an organism-wide setting in Drosophila, Mondo-Mlx controls the majority of sugar-regulated genes involved in nutrient digestion and transport as well as carbohydrate, amino acid, and lipid metabolism. Furthermore, human orthologs of the Mondo-Mlx targets display enrichment among gene variants associated with high circulating triglycerides. In addition to direct regulation of metabolic genes, Mondo-Mlx maintains metabolic homeostasis through downstream effectors, including the Activin ligand Dawdle and the Gli-similar transcription factor Sugarbabe. Sugarbabe controls a subset of Mondo-Mlx-dependent processes, including de novo lipogenesis and fatty acid desaturation. In sum, Mondo-Mlx is a master regulator of other sugar-responsive pathways essential for adaptation to a high-sugar diet.
    Full-text · Article · Oct 2015 · Cell Reports
  • Source
    • "Due to the diversion of most glucose-derived intermediates to biosynthesis, glutamine uptake is also increased in tumours to replenish the depletion of TCA cycle intermediates which are normally supplied from glucose sources and to fuel mitochondrial ATP production. Additionally, recent work has shown that under certain conditions glutamine can also play another important role in the growth of tumour cells, providing acetyl-CoA for lipid synthesis through a process known as reductive carboxylation [35] [36] [37] [38]. Similar to glucose, the expression of membrane glutamine transporters (e.g., ASCT2), in particular the high affinity isoforms, is elevated in cancer [39]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Diabetes is a disease involving metabolic derangements in multiple organs. While the spectrum of diabetic complications has been known for years, recent evidence suggests that diabetes could also contribute to the initiation and propagation of certain cancers. The mechanism(s) underlying this relationship are not completely resolved but likely involve changes in hormone and nutrient levels, as well as activation of inflammatory and stress-related pathways. Interestingly, some of the drugs used clinically to treat diabetes also appear to have antitumour effects, further highlighting the interaction between these two conditions. In this contribution we review recent literature on this emerging relationship and explore the potential mechanisms that may promote cancer in diabetic patients.
    Full-text · Article · May 2015
  • Source
    • "Fluxes of these enzymes are commonly elevated in human cancers (Friday et al., 2011). Glutaminolysis also supports the production of molecules, such as glutathione and NADPH, which protect cells from oxidative stress (DeBerardinis and Cheng, 2010; Reitzer et al., 1979; Wise and Thompson, 2010). Mounting evidence suggests that many types of cancer cells have tumor-specific redox control alterations, with increased levels of reactive oxygen species (ROS) compared with normal cells (Kawanishi et al., 2006; Stuart et al., 2014; Szatrowski and Nathan, 1991; Toyokuni et al., 1995). "
    [Show abstract] [Hide abstract]
    ABSTRACT: How mitochondrial glutaminolysis contributes to redox homeostasis in cancer cells remains unclear. Here we report that the mitochondrial enzyme glutamate dehydrogenase 1 (GDH1) is commonly upregulated in human cancers. GDH1 is important for redox homeostasis in cancer cells by controlling the intracellular levels of its product alpha-ketoglutarate and subsequent metabolite fumarate. Mechanistically, fumarate binds to and activates a reactive oxygen species scavenging enzyme glutathione peroxidase 1. Targeting GDH1 by shRNA or a small molecule inhibitor R162 resulted in imbalanced redox homeostasis, leading to attenuated cancer cell proliferation and tumor growth. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Feb 2015 · Cancer Cell
Show more