Suppression of RelA/p65 transactivation activity by a lignoid manassantin isolated from Saururus chinensis.
In our search for NF-kappaB inhibitors from natural resources, we have previously identified two structurally related dilignans, manassantin A and B as specific inhibitors of NF-kappaB activation from Saururus chinensis. However, their molecular mechanism of action remains unclear. We here demonstrate that manassantins A and B are potent inhibitors of NF-kappaB activation by the suppression of transciptional activity of RelA/p65 subunit of NF-kappaB. These compounds significantly inhibited the induced expression of NF-kappaB reporter gene by LPS or TNF-alpha in a dose-dependent manner. However, these compounds did not prevent the DNA-binding activity of NF-kappaB assessed by electrophoretic mobility shift assay as well as the induced-degradation of IkappaB-alpha protein by LPS or TNF-alpha. Further analysis revealed that manassantins A and B dose-dependently suppressed not only the induced NF-kappaB activation by overexpression of RelA/p65, but also transactivation activity of RelA/p65. Furthermore, treatment of cells with these compounds prevented the TNF-alpha-induced expression of anti-apoptotic NF-kappaB target genes Bfl-1/A1, a prosurvival Bcl-2 homologue, and resulted in sensitizing HT-1080 cells to TNF-alpha-induced cell death. Similarly, these compounds also suppressed the LPS-induced inducible nitric oxide synthase expression and nitric oxide production. Taken together, manassantins A and B could be valuable candidate for the intervention of NF-kappaB-dependent pathological condition such as inflammation and cancer.
Lee
Jeong-Hyung
JH
Korea Research Institute of Bioscience and Biotechnology, P.O. Box 115, Yuseong, 305-600 Daejeon, South Korea.
Hwang
Bang Yeon
BY
Kim
Kyung-Sook
KS
Nam
Jeong Beom
JB
Hong
Young Soo
YS
Lee
Jung Joon
JJ
D000818:Animals; D017209:Apoptosis; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D005663:Furans / Q000302:isolation & purification / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D017705:Lignans; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D015778:Minor Histocompatibility Antigens; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D032134:Saururaceae / Q000737:chemistry*; D051996:Transcription Factor RelA; D015533:Transcriptional Activation / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C096816:BCL2-related protein A1; D005663:Furans; D020672:I-kappa B Proteins; D017705:Lignans; D008070:Lipopolysaccharides; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide; C054895:manassantin A; D004247:DNA; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse