AMPK promotes antitumor immunity by downregulating PD-1 in regulatory T cells via the HMGCR/p38 signaling pathway
- Authors
- Pokhrel, Ram Hari; Acharya, Suman; Ahn, Jae-Hee; Gu, Ye; Pandit, Mahesh; Kim, Jong-Oh; Park, Yun-Yong; Kang, Ben; Ko, Hyun-Jeong; Chang, Jae-Hoon
- Issue Date
- 14-Oct-2021
- Publisher
- BMC
- Keywords
- Tregs; Tumor; PD-1; AMPK; HMGCR; Compound C; AICAR
- Citation
- MOLECULAR CANCER, v.20, no.1
- Journal Title
- MOLECULAR CANCER
- Volume
- 20
- Number
- 1
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/62121
- DOI
- 10.1186/s12943-021-01420-9
- ISSN
- 1476-4598
1476-4598
- 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 AMPK alpha 1(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 AMPK alpha 1 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-3 beta (GSK-3 beta), 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/GSK3 beta 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.
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Collections - College of Natural Sciences > Department of Life Science > 1. Journal Articles
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