Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma
Open accessAbstract
L-Glutamine (Gln) functions physiologically to balance the carbon and nitrogen requirements of tissues. It has been proposed that in cancer cells undergoing aerobic glycolysis, accelerated anabolism is sustained by Gln-derived carbons, which replenish the tricarboxylic acid (TCA) cycle (anaplerosis). However, it is shown here that in glioblastoma (GBM) cells, almost half of the Gln-derived glutamate (Glu) is secreted and does not enter the TCA cycle, and that inhibiting glutaminolysis does not affect cell proliferation. Moreover, Gln-starved cells are not rescued by TCA cycle replenishment. Instead, the conversion of Glu to Gln by glutamine synthetase (GS; cataplerosis) confers Gln prototrophy, and fuels de novo purine biosynthesis. In both orthotopic GBM models and in patients, (13)C-glucose tracing showed that GS produces Gln from TCA-cycle-derived carbons. Finally, the Gln required for the growth of GBM tumours is contributed only marginally by the circulation, and is mainly either autonomously synthesized by GS-positive glioma cells, or supplied by astrocytes.
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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 [67]
The Results section ('Primary human GBM stem-like cells are self-sufficient for Gln requirements'; page unavailable) reports that glioma stem-like cells grew without glutamine supplementation. But the Discussion (page unavailable) says glutamine remains required for growth: these cells synthesize it, while other glioblastoma cells can obtain it from astrocytes. The paper therefore supports growth without an external glutamine supply in specific models, not tumour growth without glutamine itself. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHuman glioblastoma cells do not rely much on circulating glutamine for proliferation but more on glutamate to synthesize glutamine via glutamine synthetase to fuel purine biosynthesis.
“Furthermore, human glioblastoma cells do not rely much on circulating glutamine for proliferation but rather more on glutamate to synthesize glutamine via glutamine synthetase to fuel purine biosynthesis193.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [193]
Human brain tumors are highly glutamine avid.
“Furthermore, human brain tumors are highly glutamine avid (Venneti et al., 2015) (Tardito et al., 2015).”
From Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma (2018) · cites this paper as Tardito et al., 2015
Glutamine can be used as an anaplerotic substrate in the TCA cycle, a carbon and nitrogen donor, or for production of purine and pyrimidine nucleotides necessary for DNA replication.
“Glutamine can either be used as an important anaplerotic substrate in the TCA cycle, a carbon and nitrogen donor, or for production of purine and pyrimidine nucleotides that are necessary for DNA replication (216).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [216]
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- Authors
- Tardito, S., Oudin, A., Ahmed, S. U., Fack, F., Keunen, O., Zheng, L., Miletic, H., Sakariassen, P. Ø., Weinstock, A., Wagner, A., Lindsay, S. L., Hock, A. K., Barnett, S. C., Ruppin, E., Mørkve, S. H., Lund-Johansen, M., Chalmers, A. J., Bjerkvig, R., Niclou, S. P., & Gottlieb, E.
- Affiliations
- Cancer Research UK Scotland Institute (GB)
- Luxembourg Institute of Health (LU)
- University of Glasgow (GB)
- University of Bergen (NO)
- Tel Aviv University (IL)
- Haukeland University Hospital (NO)
- Corresponding author
- Gottlieb, Eyal
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2015-11-23
- Volume
- 17
- Issue
- 12
- Pages
- 1556-1568
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC4663685
- OpenAlex
- W2174361280
- Cited by
- 557
- References
- 43
- Citations by year
- 2026: 32 · 2025: 43 · 2024: 44 · 2023: 57 · 2022: 59 · 2021: 73 · 2020: 54 · 2019: 67 · 2018: 47 · 2017: 44 · 2016: 33 · 2015: 2
- FWCI
- 13.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Sunderland Repository (University of Sunderland) (acceptedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion)
- Funders
- Cancer Research UK (A18278, 18278, A12477, 18274)
- Medical Research Council (MR/J004731/1)
- 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
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- glutamine synthetase, glioblastoma, glutamine starvation, glutamate, purine biosynthesis, cataplerosis, anaplerosis, TCA cycle, glutamine metabolism, astrocytes, tumor growth, 13C glucose tracing
- MeSH terms
- Animals, Astrocytes, Brain Neoplasms, Cells, Cultured, Citric Acid Cycle, Female, Glioblastoma, Glutamine, Glutamate-Ammonia Ligase, Humans, Male, Models, Biological, Nucleotides, Transplantation, Heterologous, Neoplastic Stem Cells, Blotting, Western, Mice, SCID, Mice, Inbred NOD, Rats, Sprague-Dawley, Glutamic Acid, Coculture Techniques, Reverse Transcriptase Polymerase Chain Reaction, Cell Line, Tumor, Cell Proliferation
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