Deguelin, an Akt inhibitor, suppresses IkappaBalpha kinase activation leading to suppression of NF-kappaB-regulated gene expression, potentiation of apoptosis, and inhibition of cellular invasion.
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.
Nair
Asha S
AS
Department of Experimental Therapeutics, Cytokine Research Laboratory, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Shishodia
Shishir
S
Ahn
Kwang Seok
KS
Kunnumakkara
Ajaikumar B
AB
Sethi
Gautam
G
Aggarwal
Bharat B
BB
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004347:Drug Interactions; D004847:Epithelial Cells / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects; D016328:NF-kappa B / Q000502:physiology*; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D012402:Rotenone / Q000031:analogs & derivatives* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000970:Antineoplastic Agents; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D012402:Rotenone; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; C107676:deguelin