Glutamine synthetase is necessary for sarcoma adaptation to glutamine deprivation and tumor growth

Sameer H. Issaq, Arnulfo Mendoza, Stephen D. Fox, Lee J. Helman

Research output: Contribution to journalArticle

Abstract

Despite a growing body of knowledge about the genomic landscape and molecular pathogenesis of sarcomas, translation of basic discoveries into targeted therapies and significant clinical gains has remained elusive. Renewed interest in altered metabolic properties of cancer cells has led to an exploration of targeting metabolic dependencies as a novel therapeutic strategy. In this study, we have characterized the dependency of human pediatric sarcoma cells on key metabolic substrates and identified a mechanism of adaptation to metabolic stress by examining proliferation and bioenergetic properties of rhabdomyosarcoma and Ewing sarcoma cells under varying concentrations of glucose and glutamine. While all cell lines tested were completely growth-inhibited by lack of glucose, cells adapted to glutamine deprivation, and restored proliferation following an initial period of reduced growth. We show that expression of glutamine synthetase (GS), the enzyme responsible for de novo glutamine synthesis, increased during glutamine deprivation, and that pharmacological or shRNA-mediated GS inhibition abolished proliferation of glutamine-deprived cells, while having no effect on cells grown under normal culture conditions. Moreover, the GS substrates and glutamine precursors glutamate and ammonia restored proliferation of glutamine-deprived cells in a GS-dependent manner, further emphasizing the necessity of GS for adaptation to glutamine stress. Furthermore, pharmacological and shRNA-mediated GS inhibition significantly reduced orthotopic xenograft tumor growth. We also show that glutamine supports sarcoma nucleotide biosynthesis and optimal mitochondrial bioenergetics. Our findings demonstrate that GS mediates proliferation of glutamine-deprived pediatric sarcomas, and suggest that targeting metabolic dependencies of sarcomas should be further investigated as a potential therapeutic strategy.

Original languageEnglish (US)
Article number20
JournalOncogenesis
Volume8
Issue number3
DOIs
StatePublished - Mar 1 2019
Externally publishedYes

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Glutamate-Ammonia Ligase
Glutamine
Sarcoma
Growth
Neoplasms
Energy Metabolism
Small Interfering RNA
Pharmacology
Pediatrics
Glucose
Physiological Stress
Ewing's Sarcoma
Rhabdomyosarcoma
Ammonia
Heterografts
Glutamic Acid
Therapeutics
Nucleotides
Cell Line

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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Glutamine synthetase is necessary for sarcoma adaptation to glutamine deprivation and tumor growth. / Issaq, Sameer H.; Mendoza, Arnulfo; Fox, Stephen D.; Helman, Lee J.

In: Oncogenesis, Vol. 8, No. 3, 20, 01.03.2019.

Research output: Contribution to journalArticle

Issaq, Sameer H. ; Mendoza, Arnulfo ; Fox, Stephen D. ; Helman, Lee J. / Glutamine synthetase is necessary for sarcoma adaptation to glutamine deprivation and tumor growth. In: Oncogenesis. 2019 ; Vol. 8, No. 3.
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