title: 4',6-Dihydroxy-4-methoxyisoaurone inhibits TNF-α-induced NF-κB activation and expressions of NF-κB-regulated target gene products.
abstract: The nuclear factor-κB (NF-κB) transcription factors control many physiological processes including inflammation, apoptosis, and angiogenesis. In our search for NF-κB inhibitors from natural resources, we identified 4',6-dihydroxy-4-methoxyisoaurone (ISOA) as an inhibitor of NF-κB activation from the seeds of Trichosanthes kirilowii. However, the mechanism by which ISOA inhibits NF-κB activation is not fully understood. In the present study, we demonstrated the effect of ISOA on NF-κB activation in TNF-α-stimulated HeLa cells. This compound suppressed NF-κB activation through the inhibition of IκB kinase (IKK) activation. ISOA also has an influence on upstream signaling of IKK through the inhibition of expression of adaptor proteins, TNF receptor-associated factor 2 (TRAF2) and receptor interacting protein 1 (RIP1). Consequently, ISOA blocked the phosphorylation and degradation of the inhibitor of NF-κB alpha (IκBα), and subsequent phosphorylation and nuclear translocation of p65. The suppression of NF-κB activation by ISOA led to the down-regulation of target genes involved in inflammation, proliferation, as well as potentiation of TNF-α-induced apoptosis. Taken together, this study extends our understanding on the mechanisms underlying the anti-inflammatory and anti-cancer activities of ISOA. Our findings provide new insight into the molecular mechanisms and a potential application of ISOA for inflammatory diseases as well as certain cancers.
authors.affiliation: Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China; Molecular Cancer Research Center, Yanbian University, Yanji 133002, Jilin Province, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Ma
authors.affiliation: Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China; Molecular Cancer Research Center, Yanbian University, Yanji 133002, Jilin Province, China.
authors.forename: Chunliu
authors.initials: C
authors.lastname: Mi
authors.affiliation: Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China; Molecular Cancer Research Center, Yanbian University, Yanji 133002, Jilin Province, China.
authors.forename: Ke Si
authors.initials: KS
authors.lastname: Wang
authors.affiliation: Molecular Cancer Research Center, Yanbian University, Yanji 133002, Jilin Province, China.
authors.forename: Jung Joon
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China; Molecular Cancer Research Center, Yanbian University, Yanji 133002, Jilin Province, China. Electronic address: xjjin@ybu.edu.cn.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Jin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects* / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D008517:Phytotherapy; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012639:Seeds / Q000737:chemistry; D012717:Sesquiterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D029778:Trichosanthes / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha
chemical_list: C550949:4',6-dihydroxy-4-methoxyisoaurone; C119724:AGFG1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; D012717:Sesquiterpenes; D047992:TNF Receptor-Associated Factor 2; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase
keywords: 4′,6-dihydroxy-4-methoxyisoaurone; Apoptosis; IκBα; NF-κB; p65