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

Tardito, S. et al. (2015) Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma. Nature Cell Biology, 17(12), pp. 1556-1568. (doi: 10.1038/ncb3272) (PMID:26595383) (PMCID:PMC4663685)

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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, 13C–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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Tardito, Dr Saverio and Chalmers, Professor Anthony and Hock, Dr Andreas and Zheng, Mr Liang and Ahmed, Dr Shafiq and Barnett, Professor Susan and Lindsay, Dr Susan and Gottlieb, Professor Eyal
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., and Gottlieb, E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Nature Cell Biology
Publisher:Nature Publishing Group
ISSN:1465-7392
ISSN (Online):1476-4679

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