title: Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma.
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.
authors.affiliation: Cancer Metabolism Research Unit, Cancer Research UK, Beatson Institute, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Saverio
authors.initials: S
authors.lastname: Tardito
authors.affiliation: NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg, Luxembourg.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Oudin
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Shafiq U
authors.initials: SU
authors.lastname: Ahmed
authors.affiliation: NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg, Luxembourg.
authors.forename: Fred
authors.initials: F
authors.lastname: Fack
authors.affiliation: NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg, Luxembourg.
authors.forename: Olivier
authors.initials: O
authors.lastname: Keunen
authors.affiliation: Cancer Metabolism Research Unit, Cancer Research UK, Beatson Institute, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Liang
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Kristian Gerhard Jebsen Brain Tumour Research Center, Department of Biomedicine, University of Bergen, Bergen N-5009, Norway.
authors.forename: Hrvoje
authors.initials: H
authors.lastname: Miletic
authors.affiliation: Kristian Gerhard Jebsen Brain Tumour Research Center, Department of Biomedicine, University of Bergen, Bergen N-5009, Norway.
authors.forename: Per Øystein
authors.initials: PØ
authors.lastname: Sakariassen
authors.affiliation: The Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Adam
authors.initials: A
authors.lastname: Weinstock
authors.affiliation: The Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Allon
authors.initials: A
authors.lastname: Wagner
authors.affiliation: Institute of Infection, Immunity and inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Lindsay
authors.affiliation: Cancer Metabolism Research Unit, Cancer Research UK, Beatson Institute, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Andreas K
authors.initials: AK
authors.lastname: Hock
authors.affiliation: Institute of Infection, Immunity and inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Barnett
authors.affiliation: 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.
authors.forename: Eytan
authors.initials: E
authors.lastname: Ruppin
authors.affiliation: Department of Neurosurgery, Haukeland University Hospital, Bergen N-5021, Norway.
authors.forename: Svein Harald
authors.initials: SH
authors.lastname: Mørkve
authors.affiliation: Department of Neurosurgery, Haukeland University Hospital, Bergen N-5021, Norway.|Department of Clinical Medicine, University of Bergen, Bergen N-5020, Norway.
authors.forename: Morten
authors.initials: M
authors.lastname: Lund-Johansen
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Chalmers
authors.affiliation: 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.
authors.forename: Rolf
authors.initials: R
authors.lastname: Bjerkvig
authors.affiliation: 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.
authors.forename: Simone P
authors.initials: SP
authors.lastname: Niclou
authors.affiliation: Cancer Metabolism Research Unit, Cancer Research UK, Beatson Institute, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Eyal
authors.initials: E
authors.lastname: Gottlieb
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D002952:Citric Acid Cycle; D018920:Coculture Techniques; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005974:Glutamate-Ammonia Ligase / Q000235:genetics / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000378:metabolism; D009711:Nucleotides / Q000096:biosynthesis*; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous
chemical_list: D009711:Nucleotides; D005973:Glutamine; D018698:Glutamic Acid; D005974:Glutamate-Ammonia Ligase