Glucose-Independent Glutamine Metabolism via TCA Cycling for Proliferation and Survival in B Cells
Open accessAbstract
Because MYC plays a causal role in many human cancers, including those with hypoxic and nutrient-poor tumor microenvironments, we have determined the metabolic responses of a MYC-inducible human Burkitt lymphoma model P493 cell line to aerobic and hypoxic conditions, and to glucose deprivation, using stable isotope-resolved metabolomics. Using [U-(13)C]-glucose as the tracer, both glucose consumption and lactate production were increased by MYC expression and hypoxia. Using [U-(13)C,(15)N]-glutamine as the tracer, glutamine import and metabolism through the TCA cycle persisted under hypoxia, and glutamine contributed significantly to citrate carbons. Under glucose deprivation, glutamine-derived fumarate, malate, and citrate were significantly increased. Their (13)C-labeling patterns demonstrate an alternative energy-generating glutaminolysis pathway involving a glucose-independent TCA cycle. The essential role of glutamine metabolism in cell survival and proliferation under hypoxia and glucose deficiency makes them susceptible to the glutaminase inhibitor BPTES and hence could be targeted for cancer therapy.
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Specific metabolic importance of glutamine in tumorigenesis and tumor growth has been reported.
“Nevertheless, the specific metabolic importance of glutamine in tumorigenesis and tumor growth has also been reported194–196”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [194]
Changes in expression of glutaminolysis genes correlate with enhanced glutaminolytic flux in lymphocytes.
“Glutamine transporters (SNAT1 and SNAT2) as well as key glutaminolysis enzymes (GLS, GPT, GOT, and GLUD) are up-regulated early after T cell activation similar to glycolysis genes (7, 9); several groups have correlated these changes in gene expression to enhanced glutaminolytic flux in lymphocytes (9, 53).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [53]
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- Authors
- Le, A., Lane, A. N., Hamaker, M., Bose, S., Gouw, A., Barbi, J., Tsukamoto, T., Rojas, C. J., Slusher, B. S., Zhang, H., Zimmerman, L. J., Liebler, D. C., Slebos, R. J. C., Lorkiewicz, P. K., Higashi, R. M., Fan, T. W. M., & Dang, C. V.
- Affiliations
- Johns Hopkins University (US)
- University of Louisville (US)
- Vanderbilt University (US)
- Abramson Cancer Center (US)
- Corresponding author
- Le, Anne
- Lane, Andrew N.
- Fan, Teresa W.M.
- Dang, Chi V.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 15
- Issue
- 1
- Pages
- 110-121
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3345194
- OpenAlex
- W2051181260
- Cited by
- 1,095
- References
- 48
- Citations by year
- 2026: 32 · 2025: 58 · 2024: 63 · 2023: 90 · 2022: 87 · 2021: 94 · 2020: 89 · 2019: 77 · 2018: 85 · 2017: 88 · 2016: 87 · 2015: 77 · 2014: 80 · 2013: 54 · 2012: 34
- FWCI
- 25.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA057341, R01CA118434, R01CA051497, P30CA016520)
- National Institute of Neurological Disorders and Stroke (R21NS074151)
- National Center for Research Resources (P20RR018733)
- 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, TCA cycle, c-Myc, Burkitt lymphoma, hypoxia, glucose deprivation, glutaminolysis, B cells, BPTES, glutaminase inhibitors, citrate, fumarate, malate, cell proliferation, cell survival, tumor microenvironment
- MeSH terms
- B-Lymphocytes, Carbon Isotopes, Cell Survival, Citric Acid Cycle, Fumarates, Glucose, Glutaminase, Glutamine, Humans, Isotope Labeling, Malates, Oxidation-Reduction, Sulfides, Thiadiazoles, Cell Hypoxia, Citric Acid, Cell Line, Tumor, Cell Proliferation
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