Deguelin, an Akt Inhibitor, Suppresses IB Kinase Activation Leading to Suppression of Nf-B-Regulated Gene Expression, Potentiation of Apoptosis, and Inhibition of Cellular Invasion

Nair, A.S.; Shishodia, S.; Ahn, K.S.; Kunnumakkara, A.B.; Sethi, G.; Aggarwal, B.B.

The Journal of Immunology 177(8): 5612-5622

2006


DOI: 10.4049/jimmunol.177.8.5612
Accession: 068490399

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Abstract
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-kappaB, we postulated that the activity of deguelin is mediated through this transcription factor. We found that deguelin suppressed NF-kappaB activation induced by carcinogens, tumor promoters, growth factors, and inflammatory stimuli. This suppression was not cell-type specific, because NF-kappaB activation was suppressed in both lymphoid and epithelial cells. Moreover, constitutive NF-kappaB activation was also blocked by deguelin. The suppression of TNF-induced NF-kappaB activation by deguelin occurred through the inhibition of the activation of IkappaBalpha kinase, leading to sequential suppression of IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, p65 nuclear translocation, and NF-kappaB-dependent reporter gene expression. Deguelin also suppressed the NF-kappaB reporter activity induced by TNFR1, TNFR-associated death domain, TNFR-associated factor 2, and IkappaBalpha kinase, but not that induced by p65. The inhibition of NF-kappaB 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-kappaB activation pathway, which may explain its role in the suppression of carcinogenesis and cellular proliferation.