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Fisetin, an inhibitor of cyclin-dependent kinase 6, down-regulates nuclear factor-kappaB-regulated cell proliferation, antiapoptotic and metastatic gene products through the suppression of TAK-1 and receptor-interacting protein-regulated IkappaBalpha kinase activation.
Mol Pharmacol. 2007 Jun; 71(6):1703-14.MP

Abstract

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-kappaB 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-kappaB and NF-kappaB-regulated gene products in vitro. We found that among nine different flavones tested, fisetin was potent in suppressing tumor necrosis factor (TNF)-induced NF-kappaB activation. Fisetin also suppressed the NF-kappaB activation induced by various inflammatory agents and carcinogens, and it blocked the phosphorylation and degradation of IkappaBalpha by inhibiting IkappaBalpha (IKK) activation, which in turn led to suppression of the phosphorylation and nuclear translocation of p65. NF-kappaB-dependent reporter gene expression was also suppressed by fisetin, as was NF-kappaB 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-kappaB-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-kappaB pathways.

Authors+Show Affiliations

Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17387141

Citation

Sung, Bokyung, et al. "Fisetin, an Inhibitor of Cyclin-dependent Kinase 6, Down-regulates Nuclear factor-kappaB-regulated Cell Proliferation, Antiapoptotic and Metastatic Gene Products Through the Suppression of TAK-1 and Receptor-interacting Protein-regulated IkappaBalpha Kinase Activation." Molecular Pharmacology, vol. 71, no. 6, 2007, pp. 1703-14.
Sung B, Pandey MK, Aggarwal BB. Fisetin, an inhibitor of cyclin-dependent kinase 6, down-regulates nuclear factor-kappaB-regulated cell proliferation, antiapoptotic and metastatic gene products through the suppression of TAK-1 and receptor-interacting protein-regulated IkappaBalpha kinase activation. Mol Pharmacol. 2007;71(6):1703-14.
Sung, B., Pandey, M. K., & Aggarwal, B. B. (2007). Fisetin, an inhibitor of cyclin-dependent kinase 6, down-regulates nuclear factor-kappaB-regulated cell proliferation, antiapoptotic and metastatic gene products through the suppression of TAK-1 and receptor-interacting protein-regulated IkappaBalpha kinase activation. Molecular Pharmacology, 71(6), 1703-14.
Sung B, Pandey MK, Aggarwal BB. Fisetin, an Inhibitor of Cyclin-dependent Kinase 6, Down-regulates Nuclear factor-kappaB-regulated Cell Proliferation, Antiapoptotic and Metastatic Gene Products Through the Suppression of TAK-1 and Receptor-interacting Protein-regulated IkappaBalpha Kinase Activation. Mol Pharmacol. 2007;71(6):1703-14. PubMed PMID: 17387141.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fisetin, an inhibitor of cyclin-dependent kinase 6, down-regulates nuclear factor-kappaB-regulated cell proliferation, antiapoptotic and metastatic gene products through the suppression of TAK-1 and receptor-interacting protein-regulated IkappaBalpha kinase activation. AU - Sung,Bokyung, AU - Pandey,Manoj K, AU - Aggarwal,Bharat B, Y1 - 2007/03/26/ PY - 2007/3/28/pubmed PY - 2007/7/19/medline PY - 2007/3/28/entrez SP - 1703 EP - 14 JF - Molecular pharmacology JO - Mol Pharmacol VL - 71 IS - 6 N2 - 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-kappaB 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-kappaB and NF-kappaB-regulated gene products in vitro. We found that among nine different flavones tested, fisetin was potent in suppressing tumor necrosis factor (TNF)-induced NF-kappaB activation. Fisetin also suppressed the NF-kappaB activation induced by various inflammatory agents and carcinogens, and it blocked the phosphorylation and degradation of IkappaBalpha by inhibiting IkappaBalpha (IKK) activation, which in turn led to suppression of the phosphorylation and nuclear translocation of p65. NF-kappaB-dependent reporter gene expression was also suppressed by fisetin, as was NF-kappaB 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-kappaB-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-kappaB pathways. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/17387141/Fisetin_an_inhibitor_of_cyclin_dependent_kinase_6_down_regulates_nuclear_factor_kappaB_regulated_cell_proliferation_antiapoptotic_and_metastatic_gene_products_through_the_suppression_of_TAK_1_and_receptor_interacting_protein_regulated_IkappaBalpha_kinase_activation_ DB - PRIME DP - Unbound Medicine ER -