Therapeutic effects of methionine sulfoximine in multiple diseases include and extend beyond inhibition of glutamine synthetase

Brusilow, William S.A.; Peters, Tyler

doi:10.1080/14728222.2017.1303484

Cited by 20 publications

(21 citation statements)

References 80 publications

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“…To determine the importance of GS activity in glutamine-deprived sarcoma proliferation, we utilized the well-characterized, irreversible GS inhibitor l -methionine sulfoximine (MSO) 29,30,34 and the GS substrates glutamate and ammonia (see schematic in Fig. 3a).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2019

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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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Section: Resultsmentioning

confidence: 99%

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

et al. 2019

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“…Therefore, it may be necessary to include a GS inhibitor. However, MSO, which is the best-characterized GS inhibitor, has been largely avoided as a clinical cancer therapeutic agent due to CNS toxicity (23). Further examination of strategies to limit CNS toxicity by MSO and GS inhibition are needed, such as combination therapy, to lower the necessary dose or tumor-specific drug delivery.…”

Section: Discussionmentioning

confidence: 99%

Glutamine metabolism in the proliferation of GS-expression pituitary tumor cells

Chen

Ding

et al. 2020

Endocrine Connections

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Objective: Many cancer cells cannot survive without exogenous glutamine (Gln); however, cancer cells expressing glutamine synthetase (GS) do not have this restriction. Previous metabolomics studies have indicated that glutamine metabolism is altered during pituitary tumorigenesis. However, the main role of Gln in pituitary adenoma (PA) pathophysiology remains unknown. The aim of this study was to evaluate the expression of GS and the main role of Gln in human PAs. Methods: We used cell proliferation assay and flow cytometry to assess the effect of Gln depletion on three different pituitary cell lines and human primary PA cells. We then investigated the expression level of Gln synthetase (GS) in 24 human PA samples. At last, we used LC-MS/MS to identify the differences in metabolites of PA cells after the blockage of both endogenous and exogenous Gln. Results: PA cell lines showed different sensitivities to Gln starvation, and the sensitivity is correlated with GS expression level. GS expressed in 21 out of the 24 human PA samples. Furthermore, a positive p53 and ki-67 index was correlated with a higher GS expression level (P < 0.05). Removal of both endogenous and exogenous Gln from GS-expressing PA cells resulted in blockage of nucleotide metabolism and cell cycle arrest. Conclusions: Our data indicate that GS is needed for PA cells to undergo proliferation during Gln deprivation, and most human PA cells express GS and might have a negative response to exogenous Gln depletion. Moreover, Gln is mainly responsible for nucleotide metabolism in the proliferation of GS-expressing pituitary tumor cells.

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“…5 A case of success is the improvement in the wood characteristics of hybrid poplar trees with increased GS1α expression. 65 was tested as an antituberculosis drug 46,47 but never reached the market (Box 3). Its use remains confined to academic research.…”

Section: Inhibitors Of Gsmentioning

confidence: 99%

“…73 Moreover, GS inhibitors appear to have a protective effect in acute liver failure (ALF) diseases, with studies being made in the ALF model mousse, by preventing the cerebral edema and astrocyte swelling caused by the increased activity of brain GS during hyperammonemia. 47,74 Diketopurine analogue 3-aminomidazol [ GS enzymes are essential to any living organism, balancing both the carbon and nitrogen content inside the cell. These enzymes are drug/herbicide targets of high interest among academia and provide proven opportunities for industrial applications, such as the blockbuster herbicide Basta ® .…”

Section: Box 3 Gs Developments On the Pharmaceutical Industrymentioning

confidence: 99%

Glutamine synthetase structure‐catalysis relationship—Recent advances and applications

Moreira

Ramos

Fernandes

2018

WIREs Comput Mol Sci

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Glutamine synthetase is a key enzyme that exists in every living organism. It is responsible for incorporating ammonium into glutamate, generating glutamine. Research on this enzyme has grown substantially over the last decades. The recent advances in the determination of its structure, through the crystallization of novel classes of glutamine synthetase with increased resolution, greatly contributed to a shift in the glutamine synthetase research from fundamental to more applied. Here, we explore the active sites of glutamine synthetases, review the structural and catalytic roles of their active sites' ions Mg 2+ s, combine the information gathered from recent computational studies dedicated to unravel their catalytic mechanisms with the hypothesis raised at the beginning of the XXI century based on experimental studies, glance at the development of competitive glutamine synthetase inhibitors, and highlight the high value of these enzymes to industry, namely in the fields of agriculture and medicine.

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Therapeutic effects of methionine sulfoximine in multiple diseases include and extend beyond inhibition of glutamine synthetase

Cited by 20 publications

References 80 publications

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

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

Glutamine metabolism in the proliferation of GS-expression pituitary tumor cells

Glutamine synthetase structure‐catalysis relationship—Recent advances and applications

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