Isopanduratin A Inhibits Tumor Necrosis Factor (TNF)-α-Induced Nuclear Factor κB Signaling Pathway by Promoting Extracellular Signal-Regulated Kinase-Dependent Ectodomain Shedding of TNF Receptor 1 in Human Lung Adenocarcinoma A549 Cells

• Published in: BioChem 2021-11, Vol.1 (3), p.174-189
• Main Authors: Moriwaki, Chihiro, Tanigaki, Riho, Miyake, Yasunobu, Vo, Nghia Trong, Nguyen, Mai Thanh Thi, Nguyen, Nhan Trung, Do, Truong Nhat Van, Nguyen, Hai Xuan, Kataoka, Takao
• Format: Article
• Language: English
• Subjects: Antibodies; Biotechnology; Cancer; ectodomain shedding; eukaryotic initiation factor 2α; extracellular signal-regulated kinase; isopanduratin A; Kinases; Phosphorylation; Proteins; tumor necrosis factor receptor 1; Tumor necrosis factor-TNF
• ISSN: 2673-6411; 2673-6411
• DOI: 10.3390/biochem1030014

Tumor necrosis factor α (TNF-α) induces the nuclear factor κB (NF-κB) signaling pathway via TNF receptor 1 (TNF-R1). We recently reported that isopanduratin A inhibited the TNF-α-induced NF-κB signaling pathway in human lung adenocarcinoma A549 cells. In the present study, we found that isopanduratin A did not inhibit the interleukin-1α-induced NF-κB signaling pathway in A549 cells. Isopanduratin A down-regulated the expression of TNF-R1 in these cells. We also revealed that isopanduratin A down-regulated the cell surface expression of TNF-R1 by promoting the cleavage of TNF-R1 into its soluble forms. TAPI-2, an inhibitor of TNF-α-converting enzyme, suppressed the inhibitory activity of isopanduratin A against the TNF-α-induced activation of NF-κB. The mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) kinase inhibitor U0126, but not the p38 MAP kinase inhibitor SB203580, blocked the ectodomain shedding of TNF-R1 induced by isopanduratin A. Consistent with this result, isopanduratin A induced the rapid phosphorylation of ERK, but not p38 MAP kinase. Isopanduratin A also promoted the phosphorylation of eukaryotic initiation factor 2α (eIF2α). The present results indicate that isopanduratin A inhibits TNF-α-induced NF-κB signaling pathway by promoting ERK-dependent ectodomain shedding of cell surface TNF-R1, and also decreases cellular TNF-R1 levels through the phosphorylation of eIF2α in A549 cells.