Abstract
Glutamine-synthetase (GS), the glutamine-synthesizing enzyme from glutamate, controls
important events including the release of inflammatory mediators, mTOR activation and
autophagy. However, its role in macrophages remains elusive. Here 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 and pyruvate carboxylase, and consequent HIF1α activation. These metabolic changes
and HIF1α accumulation in GS-inhibited macrophages promote M1 markers expression,
accompanied by the ability to boost T-cell proliferation and migration, and to impair endothelial
cell branching or cancer cell motility. Genetic deletion of macrophagic GS in tumor-bearing mice
promotes tumor vessel pruning, vascular normalization and accumulation of cytotoxic T-cells,
leading to metastasis inhibition. These data identify GS activity as mediator of the proangiogenic,
immunosuppressive and prometastatic function of M2-like macrophages and highlight the
possibility to target this enzyme in the treatment of cancer metastasis.
Lingua originale | Inglese |
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Stato di pubblicazione | Pubblicato - 2016 |
Evento | ISCAM 2016 - Bruxelles Durata: 1 gen 2016 → … |
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???event.eventtypes.event.conference??? | ISCAM 2016 |
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Città | Bruxelles |
Periodo | 1/01/16 → … |
Keywords
- glutamine synthetase
- macrophage