TY - JOUR
T1 - Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma
AU - Tardito, Saverio
AU - Oudin, Anaïs
AU - Ahmed, Shafiq U.
AU - Fack, Fred
AU - Keunen, Olivier
AU - Zheng, Liang
AU - Miletic, Hrvoje
AU - Sakariassen, Per Øystein
AU - Weinstock, Adam
AU - Wagner, Allon
AU - Lindsay, Susan L.
AU - Hock, Andreas K.
AU - Barnett, Susan C.
AU - Ruppin, Eytan
AU - Harald MØrkve, Svein
AU - Lund-Johansen, Morten
AU - Chalmers, Anthony J.
AU - Bjerkvig, Rolf
AU - Niclou, Simone P.
AU - Gottlieb, Eyal
N1 - Funding Information:
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.
Publisher Copyright:
© 2015 Macmillan Publishers Limited.
PY - 2015/11/27
Y1 - 2015/11/27
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84948701108
U2 - 10.1038/ncb3272
DO - 10.1038/ncb3272
M3 - Article
C2 - 26595383
AN - SCOPUS:84948701108
SN - 1465-7392
VL - 17
SP - 1556
EP - 1568
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 12
ER -