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Received for publication January 29, 2007.
Revised March 21, 2007.
Accepted for publication March 23, 2007.
B-Regulated Cell Proliferation, Antiapoptotic and Metastatic Gene Products Through The Suppression of TAK-1 and RIP Regulated I
B
Kinase Activation
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-
B 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-
B and NF-
B-regulated gene products in vitro. We found that among nine different flavones tested fisetin was potent in suppressing TNF-induced NF-
B activation. Fisetin also suppressed the NF-
B activation induced by various inflammatory agents and carcinogens; and blocked the phosphorylation and degradation of I
B
by inhibiting I
B
(IKK) activation, which in turn led to suppression of the phosphorylation and nuclear translocation of p65. NF-
B-dependent reporter gene expression was also suppressed by fisetin, as was NF-
B reporter activity induced by TNFR1, TRADD, TRAF2, NIK, and IKK, but not that induced by p65 transfection. Fisetin also inhibited TNF-induced TAK1 and RIP activation, events that lie upstream of IKK activation. The expression of NF-
B-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 (VEGF) 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-
B pathways.
Key words:
NFkappaB, Mechanisms of cell killing/apoptosis
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