Q's next: The diverse functions of glutamine in metabolism, cell biology and cancer

Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9063, USA.
Oncogene (Impact Factor: 8.56). 11/2009; 29(3):313-24. DOI: 10.1038/onc.2009.358
Source: PubMed

ABSTRACT 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.

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Available from: Ralph J Deberardinis, Jul 28, 2015
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    • "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). "
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    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.
    Cancer Cell 02/2015; 27(2):257-70. DOI:10.1016/j.ccell.2014.12.006 · 23.89 Impact Factor
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    • "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]. "
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    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.
    01/2015; 2015:1-11. DOI:10.1155/2015/390863
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    • "One of the possible ways to view cancer is as a type of a consumer–resource system, where both normal and cancerous cells rely on the resources provided by the host for survival and reproduction. Similarly to the proposed conceptual model, the immediate selective advantage of over-consumption of shared resources, such as glucose (Gillies et al. 2008), glutamine (DeBerardinis and Cheng 2009), phosphorus (Elser 2007), etc., by cancer cells selects for over-consumers at the expense of normal cells (the " under-consumers " ). This in turn can eventually lead to the tumor committing evolutionary suicide via exhaustion of the shared resources, in this case its host. "
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    ABSTRACT: Preserving a system's viability in the presence of diversity erosion is critical if the goal is to sustainably support biodiversity. Reduction in population heterogeneity, whether inter- or intraspecies, may increase population fragility, either decreasing its ability to adapt effectively to environmental changes or facilitating the survival and success of ordinarily rare phenotypes. The latter may result in over-representation of individuals who may participate in resource utilization patterns that can lead to over-exploitation, exhaustion, and, ultimately, collapse of both the resource and the population that depends on it. Here, we aim to identify regimes that can signal whether a consumer-resource system is capable of supporting viable degrees of heterogeneity. The framework used here is an expansion of a previously introduced consumer-resource type system of a population of individuals classified by their resource consumption. Application of the Reduction Theorem to the system enables us to evaluate the health of the system through tracking both the mean value of the parameter of resource (over)consumption, and the population variance, as both change over time. The article concludes with a discussion that highlights applicability of the proposed system to investigation of systems that are affected by particularly devastating overly adapted populations, namely cancerous cells. Potential intervention approaches for system management are discussed in the context of cancer therapies.
    Bulletin of Mathematical Biology 07/2014; 77(2). DOI:10.1007/s11538-014-9983-1 · 1.29 Impact Factor
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