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Licochalcone A inhibits interferon-gamma-induced programmed death-ligand 1 in lung cancer cells
Luo-Wei Yuan1, Xiao-Ming Jiang1, Yu-Lian Xu1
1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
Background:
Programmed death-ligand 1 (PD-L1), which can be induced by interferon-gamma (IFN-γ) in the tumor microenvironment, is a critical immune checkpoint in cancer immunotherapy. Natural products which reduce IFN-γ-induced PD-L1 might be exert immunotherapy effect. Licochalcone A (LCA), a natural compound derived from the root of Glycyrrhiza inflata Batalin. (Fabaceae), was found to interfere IFN-γ-induced PD-L1.
Purpose:
The aim of this study is to further clarify the effect and the mechanism of LCA on inhibiting IFN-γ-induced PD-L1 in lung cancer cells.
Methods:
The expression levels of PD-L1 were evaluated by flow cytometry, western blot and qRT-PCR. Click-iT protein synthesis assay and luciferase assay were used to identify the effect of LCA on protein synthesis. Jurkat T cell proliferation and apoptosis in the co-culture system were detected by flow cytometry. Flow cytometry was also applied to evaluate reactive oxygen species (ROS) generation.
Results:
LCA downregulated IFN-γ-induced PD-L1 protein expression and membrane localization in human lung cancer cells, regardless of inhibiting PD-L1 mRNA level or promoting its protein degradation. LCA decreased apoptosis and proliferative inhibition of Jurkat T cells caused by IFN-γ-induced PD-L1-expressing in A549 cells in the co-culture system. Strikingly, LCA was verified as a protein synthesis inhibitor, which reduced both cap-dependent and -independent translation. LCA inhibited PD-L1 translation, likely due to inhibition of 4EBP1 phosphorylation (Ser 65) and activation of PERK-eIF2α pathway. Furthermore, LCA induced ROS generation in a time-dependent manner in lung cancer cells. N-acetyl-L-cysteine (NAC) not only revered ROS generation triggered by LCA but also restored IFN-γ-induced expression of PD-L1. Both the inhibition of 4EBP1 phosphorylation (Ser 65) and activation of PERK-eIF2α axis triggered by LCA was restored by co-treatment with NAC.
Conclusion:
LCA abrogated IFN-γ-induced PD-L1 expression via ROS generation to abolish the protein translation, indicating that LCA has the potential to be applied in cancer immunotherapy.
Insights
Licochalcone A (LCA) inhibits programmed death-ligand 1 (PD-L1) expression in lung cancer by blocking protein synthesis via reactive oxygen species (ROS). This natural compound shows potential for enhancing cancer immunotherapy by reducing PD-L1-mediated immune suppression.
Area of Science:
- Immunology
- Pharmacology
- Molecular Biology
Background:
- Programmed death-ligand 1 (PD-L1) is a key immune checkpoint upregulated by interferon-gamma (IFN-γ) in the tumor microenvironment, hindering cancer immunotherapy.
- Natural products that can reduce IFN-γ-induced PD-L1 expression may offer therapeutic benefits.
- Licochalcone A (LCA), a compound from Glycyrrhiza inflata, has demonstrated an ability to interfere with IFN-γ-induced PD-L1.
Purpose of the Study:
- To investigate the mechanism by which LCA inhibits IFN-γ-induced PD-L1 expression in lung cancer cells.
- To elucidate the role of protein synthesis and reactive oxygen species (ROS) in LCA's effect on PD-L1.
Main Methods:
- Quantitative assessment of PD-L1 expression using flow cytometry, western blot, and qRT-PCR.
- Evaluation of protein synthesis inhibition via Click-iT assay and luciferase assay.
- Analysis of T-cell responses (proliferation, apoptosis) in co-culture systems.
- Measurement of ROS generation and assessment of the impact of N-acetyl-L-cysteine (NAC).
Main Results:
- LCA significantly downregulated IFN-γ-induced PD-L1 protein expression and membrane localization in lung cancer cells.
- LCA acts as a protein synthesis inhibitor, affecting both cap-dependent and -independent translation by inhibiting 4EBP1 phosphorylation and activating the PERK-eIF2α pathway.
- LCA-induced ROS generation was linked to PD-L1 downregulation, as NAC reversed these effects and restored PD-L1 expression.
- LCA mitigated the apoptosis and proliferative inhibition of Jurkat T cells caused by PD-L1-expressing lung cancer cells.
Conclusions:
- Licochalcone A effectively abrogates IFN-γ-induced PD-L1 expression by inhibiting protein translation through ROS generation.
- The findings suggest that LCA has significant potential as an immunotherapeutic agent for cancer treatment.
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