Deguelin, an Akt Inhibitor, Suppresses IκBα Kinase Activation Leading to Suppression of NF-κB-Regulated Gene Expression, Potentiation of Apoptosis, and Inhibition of Cellular Invasion

摘要

Deguelin, a constituent of the bark of the African plant Mundulea sericea (Leguminosae), exhibits antiproliferative and anticarcinogenic activities through a mechanism that is not well understood. Because various steps in carcinogenesis are regulated by NF-κB, we postulated that the activity of deguelin is mediated through this transcription factor. We found that deguelin suppressed NF-κB activation induced by carcinogens, tumor promoters, growth factors, and inflammatory stimuli. This suppression was not cell-type specific, because NF-κB activation was suppressed in both lymphoid and epithelial cells. Moreover, constitutive NF-κB activation was also blocked by deguelin. The suppression of TNF-induced NF-κB activation by deguelin occurred through the inhibition of the activation of IκBα kinase, leading to sequential suppression of IκBα phosphorylation, IκBα degradation, p65 phosphorylation, p65 nuclear translocation, and NF-κB-dependent reporter gene expression. Deguelin also suppressed the NF-κB reporter activity induced by TNFR1, TNFR-associated death domain, TNFR-associated factor 2, and IκBα kinase, but not that induced by p65. The inhibition of NF-κB activation thereby led to the down-regulation of gene products involved in cell survival, proliferation, and invasion. Suppression of these gene products by deguelin enhanced the apoptosis induced by TNF and chemotherapeutic agents and suppressed TNF-induced cellular invasion. Our results demonstrate that deguelin inhibits the NF-κB activation pathway, which may explain its role in the suppression of carcinogenesis and cellular proliferation.