PT  - JOURNAL ARTICLE
AU  - Bokyung Sung
AU  - Manoj K. Pandey
AU  - Bharat B. Aggarwal
TI  - Fisetin, an Inhibitor of Cyclin-Dependent Kinase 6, Down-Regulates Nuclear Factor-κB-Regulated Cell Proliferation, Antiapoptotic and Metastatic Gene Products through the Suppression of TAK-1 and Receptor-Interacting Protein-Regulated IκBα Kinase Activation
AID  - 10.1124/mol.107.034512
DP  - 2007 Jun 01
TA  - Molecular Pharmacology
PG  - 1703--1714
VI  - 71
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/71/6/1703.short
4100  - http://molpharm.aspetjournals.org/content/71/6/1703.full
SO  - Mol Pharmacol2007 Jun 01; 71
AB  - Fisetin (3,7,3′,4′-tetrahydroxyflavone) exhibits anti-inflammatory and antiproliferative effects through a mechanism that is poorly understood. Although fisetin has been cocrystalized with cyclin-dependent kinase 6 and inhibits its activity, this inhibition is not sufficient to explain various activities assigned to this flavonol. Because of the critical role of the NF-κB pathway in regulation of inflammation and proliferation of tumor cells, we postulated that fisetin modulates this pathway. To test this hypothesis, we examined the effect of fisetin on NF-κB and NF-κB-regulated gene products in vitro. We found that among nine different flavones tested, fisetin was potent in suppressing tumor necrosis factor (TNF)-induced NF-κB activation. Fisetin also suppressed the NF-κB activation induced by various inflammatory agents and carcinogens, and it blocked the phosphorylation and degradation of IκBα by inhibiting IκBα (IKK) activation, which in turn led to suppression of the phosphorylation and nuclear translocation of p65. NF-κB-dependent reporter gene expression was also suppressed by fisetin, as was NF-κB reporter activity induced by TNFR1, TRADD, TRAF2, NIK, and IKK but not that induced by p65 transfection. Fisetin also inhibited TNF-induced TAK1 and receptor-interacting protein activation, events that lie upstream of IKK activation. The expression of NF-κB-regulated gene products involved in antiapoptosis (cIAP-1/2, Bcl-2, Bcl-xL, XIAP, Survivin, and TRAF1), proliferation (cyclin D1, c-Myc, COX-2), invasion (ICAM-1 and MMP-9), and angiogenesis (vascular endothelial growth factor) were also down-regulated by fisetin. This correlated with potentiation of apoptosis induced by TNF, doxorubicin, and cisplatin. Thus, overall, our results indicate that fisetin mediates antitumor and anti-inflammatory effects through modulation of NF-κB pathways. The American Society for Pharmacology and Experimental Therapeutics