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

2015; Nature Portfolio; Volume: 17; Issue: 12 Linguagem: Inglês

10.1038/ncb3272

1476-4679

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

Mitochondrial Function and Pathology

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. Gottlieb and colleagues demonstrate that glioblastoma cell proliferation under glutamine starvation conditions depends on the glutamine-synthetase-dependent conversion of glutamate to glutamine to fuel purine biosynthesis and cell growth.