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

Oncogenesis
Sameer H IssaqLee J Helman

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 su...Continue Reading

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Citations

Dec 4, 2019·Current Opinion in Pediatrics·Sameer H Issaq, Christine M Heske
Dec 2, 2020·International Journal of Molecular Sciences·Huang-Yu YangTao-Han Lee
Oct 2, 2019·Cancer Letters·José M MatésJavier Márquez
Nov 2, 2019·Molecular Metabolism·Peter KreuzalerMariia Yuneva
Feb 12, 2021·International Journal of Molecular Sciences·Go Woon KimSo Hee Kwon
Mar 4, 2021·Proceedings of the National Academy of Sciences of the United States of America·Pei-Yun TsaiNada Y Kalaany
Jun 30, 2021·Trends in Cancer·Lin XiaoKlaartje Somers
Jul 24, 2021·Journal of Hematology & Oncology·Richard MiallotPhilippe Naquet
Sep 8, 2021·Aging·Francesco PacificoElvira Crescenzi
Nov 20, 2021·Frontiers in Oncology·Keiichiro OkudaYoshito Itoh

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Methods Mentioned

BETA
xenograft
ubiquitination

Software Mentioned

Genomics Analysis and Visualization Platform
IncuCyte Live - Cell Analysis System

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