[en] 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.
Disciplines :
Neurology
Author, co-author :
Tardito, Saverio; Cancer Metabolism Research Unit, Cancer Research UK, Beatson Institute, Switchback Road, Glasgow G61 1BD, UK
Oudin, Anaïs; NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg, Luxembourg
Ahmed, Shafiq U; Institute of Cancer Sciences, University of Glasgow, Glasgow G12 8QQ, UK
Fack, Fred; NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg, Luxembourg
Keunen, Olivier; NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg, Luxembourg
Zheng, Liang; Cancer Metabolism Research Unit, Cancer Research UK, Beatson Institute, Switchback Road, Glasgow G61 1BD, UK
Miletic, Hrvoje; Kristian Gerhard Jebsen Brain Tumour Research Center, Department of Biomedicine, University of Bergen, Bergen N-5009, Norway
Sakariassen, Per Øystein; Kristian Gerhard Jebsen Brain Tumour Research Center, Department of Biomedicine, University of Bergen, Bergen N-5009, Norway
Weinstock, Adam; The Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel
Wagner, Allon; The Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel
Lindsay, Susan L; Institute of Infection, Immunity and inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK
Hock, Andreas K; Cancer Metabolism Research Unit, Cancer Research UK, Beatson Institute, Switchback Road, Glasgow G61 1BD, UK
Barnett, Susan C; Institute of Infection, Immunity and inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK
Ruppin, Eytan; The Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel ; The Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
Mørkve, Svein Harald; Department of Neurosurgery, Haukeland University Hospital, Bergen N-5021, Norway
Lund-Johansen, Morten; Department of Neurosurgery, Haukeland University Hospital, Bergen N-5021, Norway ; Department of Clinical Medicine, University of Bergen, Bergen N-5020, Norway
Chalmers, Anthony J; Institute of Cancer Sciences, University of Glasgow, Glasgow G12 8QQ, UK
Bjerkvig, Rolf; NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg, Luxembourg ; Kristian Gerhard Jebsen Brain Tumour Research Center, Department of Biomedicine, University of Bergen, Bergen N-5009, Norway
NICLOU, Simone P. ; Kristian Gerhard Jebsen Brain Tumour Research Center, Department of Biomedicine, University of Bergen, Bergen N-5009, Norway
Gottlieb, Eyal; Cancer Metabolism Research Unit, Cancer Research UK, Beatson Institute, Switchback Road, Glasgow G61 1BD, UK
This study has been supported by Cancer Research UK. S.T. is a recipient of an AIRC/Marie Curie International Fellowship for Cancer Research. The human and animal metabolomic studies were supported by The Norwegian Cancer Society, The Norwegian Research Council, Helse Vest, Haukeland University Hospital and the K.G-Jebsen Foundation. We acknowledge A. Golebiewska, V. Baus-Talko, N. Van Den Broek, G. MacKay, C. Nixon and E. MacKenzie for excellent technical assistance and A. King for excellent editorial work.
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