AMPK promotes antitumor immunity by downregulating PD-1 in regulatory T cells via the HMGCR/p38 signaling pathway.
Mol Cancer
; 20(1): 133, 2021 10 14.
Article
em En
| MEDLINE
| ID: mdl-34649584
ABSTRACT
BACKGROUND:
AMP-activated protein kinase (AMPK) is a metabolic sensor that maintains energy homeostasis. AMPK functions as a tumor suppressor in different cancers; however, its role in regulating antitumor immunity, particularly the function of regulatory T cells (Tregs), is poorly defined.METHODS:
AMPKα1fl/flFoxp3YFP-Cre, Foxp3YFP-Cre, Rag1-/-, and C57BL/6 J mice were used for our research. Flow cytometry and cell sorting, western blotting, immuno-precipitation, immuno-fluorescence, glycolysis assay, and qRT-PCR were used to investigate the role of AMPK in suppressing programmed cell death 1 (PD-1) expression and for mechanistic investigation.RESULTS:
The deletion of the AMPKα1 subunit in Tregs accelerates tumor growth by increasing the expression of PD-1. Metabolically, loss of AMPK in Tregs promotes glycolysis and the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a key enzyme of the mevalonate pathway. Mechanistically, AMPK activates the p38 mitogen-activated protein kinase (MAPK) that phosphorylates glycogen synthase kinase-3ß (GSK-3ß), inhibiting the expression of PD-1 in Tregs.CONCLUSION:
Our study identified an AMPK regulatory mechanism of PD-1 expression via the HMGCR/p38 MAPK/GSK3ß signaling pathway. We propose that the AMPK activator can display synergic antitumor effect in murine tumor models, supporting their potential clinical use when combined with anti-PD-1 antibody, anti-CTLA-4 antibody, or a HMGCR inhibitor.Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Linfócitos T Reguladores
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Proteínas Quinases p38 Ativadas por Mitógeno
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Proteínas Quinases Ativadas por AMP
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Imunomodulação
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Receptor de Morte Celular Programada 1
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Hidroximetilglutaril-CoA Redutases
Limite:
Animals
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Humans
Idioma:
En
Revista:
Mol Cancer
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2021
Tipo de documento:
Article