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

doi:10.1038/ncb3272

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

School of Computer Science

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	1556-1568
Number of pages	13
Journal	Nature Cell Biology
Volume	17
Issue number	12
DOIs	https://doi.org/10.1038/ncb3272
State	Published - 27 Nov 2015

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Tardito, S., Oudin, A., Ahmed, S. U., Fack, F., Keunen, O., Zheng, L., Miletic, H., Sakariassen, P. Ø., Weinstock, A., Wagner, A., Lindsay, S. L., Hock, A. K., Barnett, S. C., Ruppin, E., Harald MØrkve, S., Lund-Johansen, M., Chalmers, A. J., Bjerkvig, R., Niclou, S. P., & Gottlieb, E. (2015). Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma. Nature Cell Biology, 17(12), 1556-1568. https://doi.org/10.1038/ncb3272

@article{1545296500e94e90aa0e335dddf5c548,

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.",

author = "Saverio Tardito and Ana{\"i}s Oudin and Ahmed, {Shafiq U.} and Fred Fack and Olivier Keunen and Liang Zheng and Hrvoje Miletic and Sakariassen, {Per {\O}ystein} and Adam Weinstock and Allon Wagner and Lindsay, {Susan L.} and Hock, {Andreas K.} and Barnett, {Susan C.} and Eytan Ruppin and {Harald M{\O}rkve}, Svein and Morten Lund-Johansen and Chalmers, {Anthony J.} and Rolf Bjerkvig and Niclou, {Simone P.} and Eyal Gottlieb",

note = "Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited.",

year = "2015",

month = nov,

day = "27",

doi = "10.1038/ncb3272",

language = "אנגלית",

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Tardito, S, Oudin, A, Ahmed, SU, Fack, F, Keunen, O, Zheng, L, Miletic, H, Sakariassen, PØ, Weinstock, A, Wagner, A, Lindsay, SL, Hock, AK, Barnett, SC, Ruppin, E, Harald MØrkve, S, Lund-Johansen, M, Chalmers, AJ, Bjerkvig, R, Niclou, SP & Gottlieb, E 2015, 'Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma', Nature Cell Biology, vol. 17, no. 12, pp. 1556-1568. https://doi.org/10.1038/ncb3272

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

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.

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SN - 1465-7392

VL - 17

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EP - 1568

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 12

ER -

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

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