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

Abstract

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.

Antitumor Effects of Ursolic Acid through Mediating the Inhibition of STAT3/PD-L1 Signaling in Non-Small Cell Lung Cancer Cells

“…The hallmarks of cancer mainly consist of the lost ability to induce apoptosis and the induction of angiogenesis, resulting in metastasis via tumor cell migration, invasion, and EMT. A drug that can inhibit these processes in a cancer cell will be suitable for anticancer studies [ 46 ]. We found that UA can induce cell death in A549 and H460 cells, which are both considered metastatic cancer cells.…”

Inhibition of GFAT1 in lung cancer cells destabilizes PD-L1 protein and improves immune response

“…Many natural compounds (e.g. Triptolide(20), Galic acid(21) and Resveratrol(22)) were also able to inhibit the expression of PD-L1 in cancer cells through various mechanisms. Like metformin, these compounds are multifunctional rather than just affecting the expression of PD-L1.…”

Potential Antitumor Effects of 6-Gingerol in p53-Dependent Mitochondrial Apoptosis and Inhibition of Tumor Sphere Formation in Breast Cancer Cells

“…EGFR can contribute to transformation of cellular phenotypes that enable tumor cell growth and survival [ 32 , 33 ]. EGFR signaling can also induce immune activation by activating p53 signaling, which thereby inhibits PD-L1 expression [ 34 ]. Steroid receptor coactivator (Src) is an intracellular tyrosine kinase that takes part in tumorigenesis via signaling from EGFR through association with focal adhesion kinase (FAK) [ 35 ].…”