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AMPK promotes antitumor immunity by downregulating PD-1 in regulatory T cells via the HMGCR/p38 signaling pathway
- Source :
- Molecular Cancer, Vol 20, Iss 1, Pp 1-15 (2021)
- Publication Year :
- 2021
- Publisher :
- BMC, 2021.
-
Abstract
- 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 AMPKα1 fl/fl Foxp3 YFP-Cre, Foxp3 YFP-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-3β (GSK-3β), 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/GSK3β 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.
Details
- Language :
- English
- ISSN :
- 14764598
- Volume :
- 20
- Issue :
- 1
- Database :
- Directory of Open Access Journals
- Journal :
- Molecular Cancer
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.174c1debff074d1ea4f04e0abaa734a8
- Document Type :
- article
- Full Text :
- https://doi.org/10.1186/s12943-021-01420-9