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

Abstract

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.

Cucurbitacin B Down-Regulates TNF Receptor 1 Expression and Inhibits the TNF-α-Dependent Nuclear Factor κB Signaling Pathway in Human Lung Adenocarcinoma A549 Cells

“…Translation inhibitors regulate the expression of TNF-R1 by reducing its de novo synthesis and by inducing its ectodomain shedding via the activation of ERK and/or p38 MAP kinase [49]. The TACE inhibitor TAPI-2 did not reverse the amount of TNF-R1 in isopanduratin A-treated A549 cells, which was the combined effect of enhanced ecodomain shedding and inhibited translation [48]. In contrast to isopanduration A, TAPI-2 suppressed reductions in TNF-R1 in cucurbitacin B-treated A549 cells.…”

“…Western blotting using different antibodies recognizing TNF-R1 excluded the possibility that cucurbitacin B bound to TNF-R1 in a similar manner to allantopyrone A. We recently reported that isopanduratin A, a flavonoid possessing an α,β-unsaturated carbonyl moiety, down-regulated the expression of TNF-R1 by ectodomain shedding via the extracellular signal-regulated kinase (ERK)-dependent activation of TACE and the inhibition of de novo translation via eIF2α phosphorylation [48]. Translation inhibitors regulate the expression of TNF-R1 by reducing its de novo synthesis and by inducing its ectodomain shedding via the activation of ERK and/or p38 MAP kinase [49].…”

Metabolomics-transcriptomics joint analysis: unveiling the dysregulated cell death network and developing a diagnostic model for high-grade neuroblastoma

“…Moreover, it has been proposed that TNF is implicated in tumor angiogenesis and cell death, thereby facilitating tumor advancement and metastasis ( 50 , 51 ). The activation of the TNF signaling pathway can induce the expression and activation of a diverse array of downstream molecules, including nuclear factor κB and p38 mitogen-activated protein kinase ( 52 , 53 ). Subsequent activation of these molecules exerts regulatory control over various biological processes, such as cell death.…”