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Butein, a tetrahydroxychalcone, inhibits nuclear factor (NF)-kappaB and NF-kappaB-regulated gene expression through direct inhibition of IkappaBalpha kinase beta on cysteine 179 residue.
J Biol Chem. 2007 Jun 15; 282(24):17340-50.JB

Abstract

Although butein (3,4,2',4'-tetrahydroxychalcone) is known to exhibit anti-inflammatory, anti-cancer, and anti-fibrogenic activities, very little is known about its mechanism of action. Because numerous effects modulated by butein can be linked to interference with the NF-kappaB pathway, we investigated in detail the effect of this chalcone on NF-kappaB activity. As examined by DNA binding, we found that butein suppressed tumor necrosis factor (TNF)-induced NF-kappaB activation in a dose- and time-dependent manner; suppressed the NF-kappaB activation induced by various inflammatory agents and carcinogens; and inhibited the NF-kappaB reporter activity induced by TNFR1, TRADD, TRAF2, NIK, TAK1/TAB1, and IKK-beta. We also found that butein blocked the phosphorylation and degradation of IkappaBalpha by inhibiting IkappaBalpha kinase (IKK) activation. We found the inactivation of IKK by butein was direct and involved cysteine residue 179. This correlated with the suppression of phosphorylation and the nuclear translocation of p65. In this study, butein also inhibited the expression of the NF-kappaB-regulated gene products involved in anti-apoptosis (IAP2, Bcl-2, and Bcl-xL), proliferation (cyclin D1 and c-Myc), and invasion (COX-2 and MMP-9). Suppression of these gene products correlated with enhancement of the apoptosis induced by TNF and chemotherapeutic agents; and inhibition of cytokine-induced cellular invasion. Overall, our results indicated that antitumor and anti-inflammatory activities previously assigned to butein may be mediated in part through the direct inhibition of IKK, leading to the suppression of the NF-kappaB activation pathway.

Authors+Show Affiliations

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

17439942

Citation

Pandey, Manoj K., et al. "Butein, a Tetrahydroxychalcone, Inhibits Nuclear Factor (NF)-kappaB and NF-kappaB-regulated Gene Expression Through Direct Inhibition of IkappaBalpha Kinase Beta On Cysteine 179 Residue." The Journal of Biological Chemistry, vol. 282, no. 24, 2007, pp. 17340-50.
Pandey MK, Sandur SK, Sung B, et al. Butein, a tetrahydroxychalcone, inhibits nuclear factor (NF)-kappaB and NF-kappaB-regulated gene expression through direct inhibition of IkappaBalpha kinase beta on cysteine 179 residue. J Biol Chem. 2007;282(24):17340-50.
Pandey, M. K., Sandur, S. K., Sung, B., Sethi, G., Kunnumakkara, A. B., & Aggarwal, B. B. (2007). Butein, a tetrahydroxychalcone, inhibits nuclear factor (NF)-kappaB and NF-kappaB-regulated gene expression through direct inhibition of IkappaBalpha kinase beta on cysteine 179 residue. The Journal of Biological Chemistry, 282(24), 17340-50.
Pandey MK, et al. Butein, a Tetrahydroxychalcone, Inhibits Nuclear Factor (NF)-kappaB and NF-kappaB-regulated Gene Expression Through Direct Inhibition of IkappaBalpha Kinase Beta On Cysteine 179 Residue. J Biol Chem. 2007 Jun 15;282(24):17340-50. PubMed PMID: 17439942.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Butein, a tetrahydroxychalcone, inhibits nuclear factor (NF)-kappaB and NF-kappaB-regulated gene expression through direct inhibition of IkappaBalpha kinase beta on cysteine 179 residue. AU - Pandey,Manoj K, AU - Sandur,Santosh K, AU - Sung,Bokyung, AU - Sethi,Gautam, AU - Kunnumakkara,Ajaikumar B, AU - Aggarwal,Bharat B, Y1 - 2007/04/17/ PY - 2007/4/19/pubmed PY - 2007/9/26/medline PY - 2007/4/19/entrez SP - 17340 EP - 50 JF - The Journal of biological chemistry JO - J Biol Chem VL - 282 IS - 24 N2 - Although butein (3,4,2',4'-tetrahydroxychalcone) is known to exhibit anti-inflammatory, anti-cancer, and anti-fibrogenic activities, very little is known about its mechanism of action. Because numerous effects modulated by butein can be linked to interference with the NF-kappaB pathway, we investigated in detail the effect of this chalcone on NF-kappaB activity. As examined by DNA binding, we found that butein suppressed tumor necrosis factor (TNF)-induced NF-kappaB activation in a dose- and time-dependent manner; suppressed the NF-kappaB activation induced by various inflammatory agents and carcinogens; and inhibited the NF-kappaB reporter activity induced by TNFR1, TRADD, TRAF2, NIK, TAK1/TAB1, and IKK-beta. We also found that butein blocked the phosphorylation and degradation of IkappaBalpha by inhibiting IkappaBalpha kinase (IKK) activation. We found the inactivation of IKK by butein was direct and involved cysteine residue 179. This correlated with the suppression of phosphorylation and the nuclear translocation of p65. In this study, butein also inhibited the expression of the NF-kappaB-regulated gene products involved in anti-apoptosis (IAP2, Bcl-2, and Bcl-xL), proliferation (cyclin D1 and c-Myc), and invasion (COX-2 and MMP-9). Suppression of these gene products correlated with enhancement of the apoptosis induced by TNF and chemotherapeutic agents; and inhibition of cytokine-induced cellular invasion. Overall, our results indicated that antitumor and anti-inflammatory activities previously assigned to butein may be mediated in part through the direct inhibition of IKK, leading to the suppression of the NF-kappaB activation pathway. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/17439942/Butein_a_tetrahydroxychalcone_inhibits_nuclear_factor__NF__kappaB_and_NF_kappaB_regulated_gene_expression_through_direct_inhibition_of_IkappaBalpha_kinase_beta_on_cysteine_179_residue_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)69036-6 DB - PRIME DP - Unbound Medicine ER -