4′,6-Dihydroxy-4-methoxyisoaurone inhibits TNF-α-induced NF-κB activation and expressions of NF-κB-regulated target gene products

• Published in: Journal of pharmacological sciences Vol. 130; no. 2; pp. 43 - 50
• Main Authors: Ma, Juan, Mi, Chunliu, Wang, Ke Si, Lee, Jung Joon, Jin, Xuejun
• Format: Journal Article
• Language: English
• Published: Japan Elsevier B.V 01.02.2016; Elsevier
• Subjects: 4′,6-dihydroxy-4-methoxyisoaurone; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Cell Proliferation - drug effects; Cell Proliferation - genetics; Gene Expression - drug effects; Gene Expression - genetics; HeLa Cells; Humans; I-kappa B Kinase - antagonists & inhibitors; Inflammation - drug therapy; Inflammation - genetics; IκBα; Neoplasms - drug therapy; Neoplasms - genetics; NF-kappa B - metabolism; NF-κB; Nuclear Pore Complex Proteins - genetics; Nuclear Pore Complex Proteins - metabolism; p65; Phosphorylation - drug effects; Phytotherapy; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Seeds - chemistry; Sesquiterpenes - isolation & purification; Sesquiterpenes - pharmacology; TNF Receptor-Associated Factor 2 - genetics; TNF Receptor-Associated Factor 2 - metabolism; Transcription Factor RelA - metabolism; Trichosanthes - chemistry; Tumor Necrosis Factor-alpha; TNFR; COX-2; VEGF; TRADD; IKK; cIAP1; TRAF2; ICAM-1; IL-8; FLIP; p65; IκBα; 4′,6-dihydroxy-4-methoxyisoaurone; NF-κB; Topo-I; MCP1; TNF-α; TAK1; Bcl2; iNOS; FADD; ISOA; RIP1; Apoptosis
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1016/j.jphs.2015.10.002

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.