The Inhibitory Mechanisms of Tumor PD-L1 Expression by Natural Bioactive Gallic Acid in Non-Small-Cell Lung Cancer (NSCLC) Cells

Non-small-cell lung cancer (NSCLC) is the most common lung cancer subtype and accounts for more than 80% of all lung cancer cases. Epidermal growth factor receptor (EGFR) phosphorylation by binding growth factors such as EGF activates downstream prooncogenic signaling pathways including KRAS-ERK, JA...

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Bibliographic Details
Published in:Cancers 2020-03, Vol.12 (3), p.727
Main Authors: Kang, Dong Young, Sp, Nipin, Jo, Eun Seong, Rugamba, Alexis, Hong, Dae Young, Lee, Hong Ghi, Yoo, Ji-Seung, Liu, Qing, Jang, Kyoung-Jin, Yang, Young Mok
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
AKT protein
Angiogenesis
Apoptosis
Binding sites
Cell culture
Cell cycle
Cell growth
Cell migration
Chemotherapy
Cytotoxicity
Epidermal growth factor
Epidermal growth factor receptors
Gallic acid
Growth factors
Immunotherapy
Kinases
Ligands
Lung cancer
Monoclonal antibodies
Non-small cell lung carcinoma
p53 Protein
PD-1 protein
PD-L1 protein
Peripheral blood
Phosphorylation
Proteins
Signal transduction
Small cell lung carcinoma
Studies
Trihydroxybenzoic acid
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Summary:Non-small-cell lung cancer (NSCLC) is the most common lung cancer subtype and accounts for more than 80% of all lung cancer cases. Epidermal growth factor receptor (EGFR) phosphorylation by binding growth factors such as EGF activates downstream prooncogenic signaling pathways including KRAS-ERK, JAK-STAT, and PI3K-AKT. These pathways promote the tumor progression of NSCLC by inducing uncontrolled cell cycle, proliferation, migration, and programmed death-ligand 1 (PD-L1) expression. New cytotoxic drugs have facilitated considerable progress in NSCLC treatment, but side effects are still a significant cause of mortality. Gallic acid (3,4,5-trihydroxybenzoic acid; GA) is a phenolic natural compound, isolated from plant derivatives, that has been reported to show anticancer effects. We demonstrated the tumor-suppressive effect of GA, which induced the decrease of PD-L1 expression through binding to EGFR in NSCLC. This binding inhibited the phosphorylation of EGFR, subsequently inducing the inhibition of PI3K and AKT phosphorylation, which triggered the activation of p53. The p53-dependent upregulation of miR-34a induced PD-L1 downregulation. Further, we revealed the combination effect of GA and anti-PD-1 monoclonal antibody in an NSCLC-cell and peripheral blood mononuclear-cell coculture system. We propose a novel therapeutic application of GA for immunotherapy and chemotherapy in NSCLC.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers12030727