1′-Acetoxychavicol Acetate Selectively Downregulates Tumor Necrosis Factor Receptor-Associated Factor 2 (TRAF2) Expression

TL;DR

This study shows that ACA, a natural compound, inhibits the NF-κB pathway by selectively reducing TRAF2 protein levels in cancer cells.

Contribution

The first demonstration that ACA selectively downregulates TRAF2 protein expression.

Findings

ACA reduces TNF-α-induced ICAM-1 expression and NF-κB signaling in A549 cells.

ACA selectively downregulates TRAF2 protein without affecting other pathway components.

TRAF2 reduction by ACA is mediated through proteasome activity.

Abstract

1′-Acetoxychavicol acetate (ACA) is a natural compound derived from rhizomes of the Zingiberaceae family that suppresses the nuclear factor κB (NF-κB) signaling pathway; however, the underlying mechanisms remain unclear. Therefore, the present study investigated the molecular mechanisms by which ACA inhibits the NF-κB signaling pathway in human lung adenocarcinoma A549 cells. The results obtained showed ACA decreased tumor necrosis factor (TNF)-α-induced intercellular adhesion molecule-1 (ICAM-1) expression in A549 cells. It also inhibited TNF-α-induced ICAM-1 mRNA expression and ICAM-1 promoter-driven and NF-κB-responsive luciferase reporter activities. Furthermore, the TNF-α-induced degradation of the inhibitor of NF-κB α protein in the NF-κB signaling pathway was suppressed by ACA. Although ACA did not affect TNF receptor 1, TNF receptor-associated death domain, or receptor-interacting protein kinase 1 protein expression, it selectively downregulated TNF receptor-associated factor 2 (TRAF2) protein expression. The proteasome inhibitor MG-132, but not inhibitors of caspases or lysosomal degradation, attenuated ACA-induced reductions in TRAF2 expression. ACA also downregulated TRAF2 protein expression in human fibrosarcoma HT-1080 cells. This is the first study to demonstrate that ACA selectively downregulates TRAF2 protein expression.

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