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Nat Cell Biol. 2015 Dec;17(12):1556-68. doi: 10.1038/ncb3272. Epub 2015 Nov 23.

Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma.

Author information

1
Cancer Metabolism Research Unit, Cancer Research UK, Beatson Institute, Switchback Road, Glasgow G61 1BD, UK.
2
NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg, Luxembourg.
3
Institute of Cancer Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
4
Kristian Gerhard Jebsen Brain Tumour Research Center, Department of Biomedicine, University of Bergen, Bergen N-5009, Norway.
5
The Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel.
6
Institute of Infection, Immunity and inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK.
7
The Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
8
Department of Neurosurgery, Haukeland University Hospital, Bergen N-5021, Norway.
9
Department of Clinical Medicine, University of Bergen, Bergen N-5020, Norway.

Abstract

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.

Comment in

PMID:
26595383
PMCID:
PMC4663685
DOI:
10.1038/ncb3272
[Indexed for MEDLINE]
Free PMC Article

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