Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis
Open accessAbstract
Tumor cell proliferation requires rapid synthesis of macromolecules including lipids, proteins, and nucleotides. Many tumor cells exhibit rapid glucose consumption, with most of the glucose-derived carbon being secreted as lactate despite abundant oxygen availability (the Warburg effect). Here, we used 13 C NMR spectroscopy to examine the metabolism of glioblastoma cells exhibiting aerobic glycolysis. In these cells, the tricarboxylic acid (TCA) cycle was active but was characterized by an efflux of substrates for use in biosynthetic pathways, particularly fatty acid synthesis. The success of this synthetic activity depends on activation of pathways to generate reductive power (NADPH) and to restore oxaloacetate for continued TCA cycle function (anaplerosis). Surprisingly, both these needs were met by a high rate of glutamine metabolism. First, conversion of glutamine to lactate (glutaminolysis) was rapid enough to produce sufficient NADPH to support fatty acid synthesis. Second, despite substantial mitochondrial pyruvate metabolism, pyruvate carboxylation was suppressed, and anaplerotic oxaloacetate was derived from glutamine. Glutamine catabolism was accompanied by secretion of alanine and ammonia, such that most of the amino groups from glutamine were lost from the cell rather than incorporated into other molecules. These data demonstrate that transformed cells exhibit a high rate of glutamine consumption that cannot be explained by the nitrogen demand imposed by nucleotide synthesis or maintenance of nonessential amino acid pools. Rather, glutamine metabolism provides a carbon source that facilitates the cell's ability to use glucose-derived carbon and TCA cycle intermediates as biosynthetic precursors.
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Evidence for the necessity of glutamine for cancer progression is conflicted: some studies report tumours can grow well without glutamine, while others show cancers are glutamine-addicted.
“The evidence for the necessity of glutamine for cancer progression is conflicted: some studies have reported that tumours can grow well without glutamine [66,67], while others showed that cancers are glutamine-addicted [68,69,70].”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [69]
The Results report that glutamine supplied anaplerosis and supported NADPH production in proliferating glioblastoma cells; the Discussion says cultured tumor cells require substantial glutamine. But the paper studies glutamine metabolism in an SF188 cell line, not whether cancers fail to grow without glutamine. It therefore supports substantial glutamine use, but does not establish the cited claim of glutamine addiction. (LLM, conf=0.83)
Experimental — accuracy not yet measuredGlutamine is an important nitrogen donor for amino acids and nucleotides, but glutamine uptake can exceed the nitrogen requirement of some cancer cells.
“Glutamine is an important nitrogen donor for amino acids and nucleotides (Hosios et al., 2016), but glutamine uptake can exceed the nitrogen requirement of some cancer cells (DeBerardinis et al., 2007).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as DeBerardinis et al., 2007
Glutamine is the preferred anaplerotic substrate in most proliferating cells growing in culture.
“The preferred anaplerotic substrate in most proliferating cells growing in culture is glutamine, the most abundant circulating amino acid in mammals (30, 72, 73, 74).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [73]
Most proliferating cells depend on continuous glutamine supply to maintain integrity of TCA cycle intermediates.
“Most proliferating cells depend on a continuous supply of glutamine to maintain the integrity of TCA cycle intermediates (DeBerardinis et al., 2007).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as DeBerardinis et al., 2007
Glutamine anaplerosis is critical for meeting the energetic requirements of proliferative cells, such as T cells during the transition from quiescent naïve T cells to effector cells, and in cancers, particularly with MYC elevation.
“Glutamine anaplerosis is critical for meeting the energetic requirements of proliferative cells, such as T cells during the transition from quiescent naïve T cells to effector cells, and in cancers, particularly with MYC elevation.32,36,37”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [32]
Carbon-tracing experiments using proliferating glioblastoma cells have established that both glucose and glutamine contribute to mitochondrial citrate pools and subsequent lipid synthesis.
“Carbon-tracing experiments using proliferating glioblastoma cells have established that both glucose and glutamine contribute to mitochondrial citrate pools and subsequent lipid synthesis (69).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [69]
Critical fluxes have been quantified in cultured cancer cells and methods for these analyses continue to improve.
“critical fluxes have been quantified in cultured cancer cells and methods for these analyses continue to improve (DeBerardinis et al., 2007; Mancuso et al., 2004; Yuan et al., 2008)”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as DeBerardinis et al., 2007
Metabolic flux studies in cancer cells have validated the model that aggressive tumor growth requires metabolic restructuring, emphasizing integration of glycolysis, glutamine metabolism and fatty acid synthesis.
“Metabolic flux studies in cancer cells have validated this model, emphasizing the integration of these three core pathways (DeBerardinis et al., 2007).”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as DeBerardinis et al., 2007
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References 30 · Cited by 2,622
Research works printed but not linked: 6
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- Authors
- DeBerardinis, R. J., Mancuso, A., Daikhin, E., Nissim, I., Yudkoff, M., Wehrli, S., & Thompson, C. B.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Abramson Cancer Center (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-12-04
- Volume
- 104
- Issue
- 49
- Pages
- 19345-19350
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2148292
- OpenAlex
- W1996365670
- Cited by
- 2,622
- References
- 30
- Citations by year
- 2026: 103 · 2025: 105 · 2024: 155 · 2023: 157 · 2022: 180 · 2021: 193 · 2020: 185 · 2019: 174 · 2018: 148 · 2017: 168 · 2016: 182 · 2015: 170 · 2014: 168 · 2013: 134 · 2012: 124
- FWCI
- 19.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P01CA104838)
- National Institute of General Medical Sciences (T32GM008638)
- National Institute of Diabetes and Digestive and Kidney Diseases (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, aerobic glycolysis, Warburg effect, glioblastoma, TCA cycle, anaplerosis, oxaloacetate, NADPH, fatty acid synthesis, glutaminolysis, pyruvate carboxylation, amino acid secretion, ammonia secretion, macromolecular synthesis, cancer metabolism
- MeSH terms
- Aerobiosis, Brain Neoplasms, Cell Transformation, Neoplastic, Citric Acid Cycle, Glioblastoma, Glucose, Glutamine, Glycolysis, Humans, Nucleotides, Protein Biosynthesis, Cell Line, Tumor, Cell Proliferation
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