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Updated: Jan 28, 2026
Glutamine Flux Imaging Using Genetically Encoded Sensors
Published on: July 31, 2014
Glutamine synthetase is necessary for sarcoma adaptation to glutamine deprivation and tumor growth
Sameer H Issaq1, Arnulfo Mendoza2, Stephen D Fox3
1Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. issaqsh@mail.nih.gov.
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.
Insights
Pediatric sarcoma cells adapt to glutamine deprivation by increasing glutamine synthetase (GS). Inhibiting GS blocks proliferation in these adapted cells, offering a potential therapeutic target for sarcoma treatment.
Area of Science:
- Oncology
- Cancer Metabolism
- Molecular Biology
Background:
- Translating genomic and molecular insights into effective sarcoma therapies remains challenging.
- Cancer cells exhibit altered metabolic properties, presenting opportunities for novel therapeutic strategies.
- Targeting metabolic dependencies is an emerging approach in cancer treatment.
Purpose of the Study:
- To characterize the metabolic substrate dependencies of human pediatric sarcoma cells.
- To investigate the adaptive mechanisms of sarcoma cells under metabolic stress, specifically glutamine deprivation.
- To evaluate glutamine synthetase (GS) as a potential therapeutic target in pediatric sarcomas.
Main Methods:
- Examined proliferation and bioenergetic properties of rhabdomyosarcoma and Ewing sarcoma cells under varying glucose and glutamine concentrations.
- Assessed the role of glutamine synthetase (GS) using pharmacological inhibition and shRNA-mediated knockdown.
- Investigated the effect of GS substrates (glutamate, ammonia) on cell proliferation.
- Evaluated the impact of GS inhibition on orthotopic xenograft tumor growth in vivo.
- Analyzed glutamine's role in nucleotide biosynthesis and mitochondrial bioenergetics.
Main Results:
- Pediatric sarcoma cells are growth-inhibited by glucose deprivation but adapt to glutamine deprivation.
- Glutamine deprivation increases the expression of glutamine synthetase (GS).
- Pharmacological or shRNA-mediated inhibition of GS abolished proliferation in glutamine-deprived cells.
- GS substrates (glutamate, ammonia) restored proliferation in glutamine-deprived cells in a GS-dependent manner.
- GS inhibition significantly reduced orthotopic xenograft tumor growth.
- Glutamine supports nucleotide biosynthesis and mitochondrial function in sarcomas.
Conclusions:
- Glutamine synthetase (GS) is crucial for the proliferation of glutamine-deprived pediatric sarcoma cells.
- Targeting metabolic dependencies, specifically GS, represents a promising therapeutic strategy for pediatric sarcomas.
- Further investigation into targeting sarcoma metabolic vulnerabilities is warranted for clinical application.
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