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Pharmacologic or Genetic Targeting of Glutamine Synthetase Skews Macrophages toward an M1-like Phenotype and Inhibits Tumor Metastasis.
Pharmacologic or Genetic Targeting of Glutamine Synthetase Skews Macrophages toward an M1-like Phenotype and Inhibits Tumor Metastasis.
- Source :
-
Cell reports [Cell Rep] 2017 Aug 15; Vol. 20 (7), pp. 1654-1666. - Publication Year :
- 2017
-
Abstract
- Glutamine-synthetase (GS), the glutamine-synthesizing enzyme from glutamate, controls important events, including the release of inflammatory mediators, mammalian target of rapamycin (mTOR) activation, and autophagy. However, its role in macrophages remains elusive. We report that pharmacologic inhibition of GS skews M2-polarized macrophages toward the M1-like phenotype, characterized by reduced intracellular glutamine and increased succinate with enhanced glucose flux through glycolysis, which could be partly related to HIF1α activation. As a result of these metabolic changes and HIF1α accumulation, GS-inhibited macrophages display an increased capacity to induce T cell recruitment, reduced T cell suppressive potential, and an impaired ability to foster endothelial cell branching or cancer cell motility. Genetic deletion of macrophagic GS in tumor-bearing mice promotes tumor vessel pruning, vascular normalization, accumulation of cytotoxic T cells, and metastasis inhibition. These data identify GS activity as mediator of the proangiogenic, immunosuppressive, and pro-metastatic function of M2-like macrophages and highlight the possibility of targeting this enzyme in the treatment of cancer metastasis.<br /> (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Cell Differentiation
Cell Line, Tumor
Cell Movement drug effects
Endothelial Cells drug effects
Endothelial Cells immunology
Endothelial Cells pathology
Glucose metabolism
Glutamate-Ammonia Ligase deficiency
Glutamine metabolism
Glycolysis drug effects
Glycolysis genetics
Humans
Hypoxia-Inducible Factor 1, alpha Subunit genetics
Hypoxia-Inducible Factor 1, alpha Subunit immunology
Injections, Subcutaneous
Interleukin-10 genetics
Interleukin-10 immunology
Leukemia, Lymphocytic, Chronic, B-Cell genetics
Leukemia, Lymphocytic, Chronic, B-Cell immunology
Leukemia, Lymphocytic, Chronic, B-Cell pathology
Lung Neoplasms genetics
Lung Neoplasms immunology
Lung Neoplasms secondary
Macrophages drug effects
Macrophages immunology
Macrophages pathology
Mice
Mice, Knockout
Monocytes drug effects
Monocytes immunology
Monocytes pathology
Neovascularization, Pathologic genetics
Neovascularization, Pathologic immunology
Neovascularization, Pathologic pathology
Primary Cell Culture
Succinic Acid metabolism
T-Lymphocytes, Cytotoxic drug effects
T-Lymphocytes, Cytotoxic immunology
T-Lymphocytes, Cytotoxic pathology
Enzyme Inhibitors pharmacology
Glutamate-Ammonia Ligase genetics
Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
Lung Neoplasms drug therapy
Methionine Sulfoximine pharmacology
Neovascularization, Pathologic prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 20
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 28813676
- Full Text :
- https://doi.org/10.1016/j.celrep.2017.07.054