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

Saverio Tardito, Anaïs Oudin, Shafiq U. Ahmed, Fred Fack, Olivier Keunen, Liang Zheng, Hrvoje Miletic, Per Øystein Sakariassen, Adam Weinstock, Allon Wagner, Susan L. Lindsay, Andreas K. Hock, Susan C. Barnett, Eytan Ruppin, Svein Harald MØrkve, Morten Lund-Johansen, Anthony J. Chalmers, Rolf Bjerkvig, Simone P. Niclou, Eyal Gottlieb*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

302 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1556-1568
Number of pages13
JournalNature Cell Biology
Volume17
Issue number12
DOIs
Publication statusPublished - 27 Nov 2015

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