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

Tardito, S, Oudin, A, Ahmed, Shafiq, Fack, F, Keunen, O, Zheng, L, Miletic, H, Sakariassen, P, Weinstock, A, Wagner, A, Lindsay, S, Hock, A, Barnett, S, Ruppin, E, Morkve, S, Lund-Johansen, M, Chalmers, A, Bjerkvig, R, Niclou, S and Gottlieb, E (2015) Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restriced glioblastoma. Nature Cell Biology, 17 (12). pp. 1556-1568.

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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, (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.

Item Type: Article
Subjects: Sciences
Divisions: Faculty of Applied Sciences
Faculty of Applied Sciences > Department of Pharmacy Health and Wellbeing
Health Sciences and Wellbeing Beacon
Depositing User: Paula Normington
Date Deposited: 12 Feb 2016 12:46
Last Modified: 20 Sep 2017 05:27
URI: http://sure.sunderland.ac.uk/id/eprint/6005

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