Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer
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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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Cancer cells proliferating in vitro consume glutamine far in excess of any other amino acid and are often dependent on extracellular glutamine for survival.
“Glutamine is a non-essential amino acid, and yet cancer cells proliferating in vitro consume glutamine far in excess of any other amino acid and are often dependent on extracellular glutamine for survival (DeBerardinis and Cheng, 2010; Eagle, 1955; Jain et al., 2012).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as DeBerardinis and Cheng, 2010
Anaplerosis replenishes TCA cycle intermediates such as citrate, increasing their availability for fatty acid and cholesterol biosynthesis.
“The process of anaplerosis replenishes metabolic intermediates removed from the TCA cycle, such as citrate, thereby increasing their availability for fatty acid and cholesterol biosynthesis53.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [53]
Aerobic glycolysis is not a symptom of impaired mitochondrial function.
“The major findings are that aerobic glycolysis is not a symptom of impaired mitochondrial function, and that glutamine supports mitochondrial oxidative metabolism when pyruvate derived from glucose is converted into lactate and secreted2–4.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [2]
Glutamine supports mitochondrial oxidative metabolism when pyruvate derived from glucose is converted into lactate and secreted.
“The major findings are that aerobic glycolysis is not a symptom of impaired mitochondrial function, and that glutamine supports mitochondrial oxidative metabolism when pyruvate derived from glucose is converted into lactate and secreted2–4.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [2]
Glutamine serves as an anaplerosis substrate to fuel the TCA cycle for energy generation and provides nitrogen for protein synthesis.
“Glutamine serves as an anaplerosis substrate to fuel the TCA cycle for energy generation and also provides nitrogen for protein synthesis (Dang, 2010; Wise and Thompson, 2010; DeBerardinis and Cheng, 2010; Daye and Wellen, 2012; Gaglio et al., 2009; Johnson et al., 2003; Rajagopalan and DeBerardinis, 2011; Shanware et al., 2011; Weinberg et al., 2010).”
From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as DeBerardinis and Cheng, 2010
The catabolism of glutamine often starts in the mitochondria and its carbon and nitrogen atoms are distributed into macromolecules throughout the cell, including TCA cycle intermediates, amino acids, nucleotides, glutathione, and lipids.
“The catabolism of glutamine, the most abundant amino acid, often starts in the mitochondria and its carbon and nitrogen atoms are distributed into macromolecules throughout the cell, including TCA cycle intermediates (important in bioenergetics), amino acids, nucleotides, glutathione, and lipids.31”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [31]
GLS inhibition suppresses proliferation.
“GLS inhibition suppresses proliferation, and GLS inhibitors are being evaluated in clinical studies for a number of cancers.31,38,39”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [31]
Tumor tissue has additional metabolic characteristics, most consistently the tendency to metabolize glutamine and to synthesize fatty acids, both of which promote tumor growth in experimental models.
“Other work has identified additional metabolic characteristics of tumor tissue, most consistently the tendency to metabolize glutamine and to synthesize fatty acids, both of which promote tumor growth in experimental models (DeBerardinis and Cheng, 2010; Swinnen et al., 2006).”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as DeBerardinis and Cheng, 2010
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- Authors
- DeBerardinis, R. J., & Cheng, T.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- DeBerardinis, R J
- ORCID
- DeBerardinis, R J
- Venue
- Oncogene
- Published
- 2009-11-02
- Volume
- 29
- Issue
- 3
- Pages
- 313-324
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC2809806
- OpenAlex
- W2060592426
- Cited by
- 1,365
- References
- 86
- Citations by year
- 2026: 65 · 2025: 84 · 2024: 96 · 2023: 80 · 2022: 109 · 2021: 100 · 2020: 98 · 2019: 82 · 2018: 96 · 2017: 106 · 2016: 88 · 2015: 90 · 2014: 83 · 2013: 70 · 2012: 58
- FWCI
- 2.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK072565, K08DK072565)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- glutamine metabolism, cancer metabolism, glutamine uptake, c-Myc, aerobic glycolysis, oxidative stress, tumor growth, whole-body metabolism, signaling pathways
- MeSH terms
- Cell Survival, Citric Acid Cycle, Energy Metabolism, Glucose, Glutamine, Humans, Models, Biological, Neoplasms, Signal Transduction, Cell Proliferation
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