Journal
JOURNAL OF IMMUNOLOGY
Volume 177, Issue 8, Pages 5612-5622Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.177.8.5612
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Funding
- NCI NIH HHS [P50CA-97007, P01 CA-91844] Funding Source: Medline
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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-kappa B, we postulated that the activity of deguelin is mediated through this transcription factor. We found that deguelin suppressed NF-kappa B activation induced by carcinogens, tumor promoters, growth factors, and inflammatory stimuli. This suppression was not cell-type specific,. because NF-kappa B activation was suppressed in both lymphoid and epithelial cells. Moreover, constitutive NF-kappa B activation was also blocked by deguelin. The suppression of TNF-induced NF-kappa B activation by deguelin occurred through the inhibition of the activation of I kappa B alpha kinase, leading to sequential suppression of I kappa B alpha phosphorylation, I kappa B alpha degradation, p65 phosphorylation, p65 nuclear translocation, and NF-kappa B-dependent reporter gene expression. Deguelin also suppressed the NF-kappa B reporter activity induced by TNFR1, TNFR-associated death domain, TNFR-associated factor 2, and I kappa B alpha kinase, but not that induced by p65. The inhibition of NF-kappa B 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-kappa B activation pathway, which may explain its role in the suppression of carcinogenesis and cellular proliferation.
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