ArticleOncogenesis2019
Glutamine synthetase is necessary for sarcoma adaptation to glutamine deprivation and tumor growth.
Article in Oncogenesis, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 50 citations in OpenAlex.
- Targeting glutamine metabolism to modulate macrophage functions in the tumor microenvironment.Discover oncology · 2026Review
- New Approaches to Investigate Novel Agents in Ewing Sarcoma: A Report From the Children's Oncology Group Bone Tumor Committee.Pediatric blood & cancer · 2025Review
- Amino acid metabolism in breast cancer: pathogenic drivers and therapeutic opportunities.Protein & cell · 2025Review
- Article
- HDAC6 and USP9X Control Glutamine Metabolism by Stabilizing GS to Promote Glioblastoma Tumorigenesis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Glutamine Synthetase: Diverse Regulation and Functions of an Ancient Enzyme.Biochemistry · 2025Review
- Article
- Targeting cellular adaptive responses to glutaminolysis perturbation for cancer therapy.Molecules and cells · 2024Review
- Targeting glutamine metabolism improves sarcoma response to radiation therapy in vivo.Communications biology · 2024Article
- Glutamine addiction in tumor cell: oncogene regulation and clinical treatment.Cell communication and signaling : CCS · 2024Review
- Modeling phenotypic heterogeneity towards evolutionarily inspired osteosarcoma therapy.Scientific reports · 2023Article
- Inhibition of NAD+-Dependent Metabolic Processes Induces Cellular Necrosis and Tumor Regression in Rhabdomyosarcoma Models.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- Glutamine Metabolism in Cancer Stem Cells: A Complex Liaison in the Tumor Microenvironment.International journal of molecular sciences · 2023Review
- Glutamine deprivation impairs function of infiltrating CD8World journal of gastrointestinal oncology · 2022Article
- Glutamine-dependent signaling controls pluripotent stem cell fate.Developmental cell · 2022Article
- Leukemia Cells Resistant to Glutamine Deprivation Express Glutamine Synthetase ProteinTurkish journal of haematology : official journal of Turkish Society of Haematology · 2022Article
- 18F-Fluorodeoxyglucose Positron Emission Tomography Is Useful in the Evaluation of Prognosis in Retroperitoneal Sarcoma.Cancers · 2021Article
- SREBP1-Induced Glutamine Synthetase Triggers a Feedforward Loop to Upregulate SREBP1 through Sp1 O-GlcNAcylation and Augments Lipid Droplet Formation in Cancer Cells.International journal of molecular sciences · 2021Article
- Article
- Metabolic landscapes in sarcomas.Journal of hematology & oncology · 2021Review
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.