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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. ISSN 1465-7392

Item Type: Article

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.

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Depositing User: Paula Normington

Identifiers

Item ID: 6005
Identification Number: https://doi.org/10.1038/ncb3272
ISSN: 1465-7392
URI: http://sure.sunderland.ac.uk/id/eprint/6005
Official URL: https://www.nature.com/articles/ncb3272

Users with ORCIDS

ORCID for Shafiq Ahmed: ORCID iD orcid.org/0000-0001-8701-6889

Catalogue record

Date Deposited: 12 Feb 2016 12:46
Last Modified: 04 Feb 2021 18:58

Contributors

Author: Shafiq Ahmed ORCID iD
Author: S Tardito
Author: A Oudin
Author: F Fack
Author: O Keunen
Author: L Zheng
Author: H Miletic
Author: P Sakariassen
Author: A Weinstock
Author: A Wagner
Author: S Lindsay
Author: A Hock
Author: S Barnett
Author: E Ruppin
Author: S Morkve
Author: M Lund-Johansen
Author: A Chalmers
Author: R Bjerkvig
Author: S Niclou
Author: E Gottlieb

University Divisions

Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences

Subjects

Sciences

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