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Identification of a novel blocker of I kappa B alpha kinase that enhances cellular apoptosis and inhibits cellular invasion through suppression of NF-kappa B-regulated gene products.
J Immunol. 2005 Jun 01; 174(11):7383-92.JI

Abstract

1'-Acetoxychavicol acetate (ACA), extracted from rhizomes of the commonly used ethno-medicinal plant Languas galanga, has been found to suppress chemical- and virus-induced tumor initiation and promotion through a poorly understood mechanism. Because several genes that regulate cellular proliferation, carcinogenesis, metastasis, and survival are regulated by activation of the transcription factor NF-kappaB, we postulated that ACA might mediate its activity through modulation of NF-kappaB activation. For this report, we investigated the effect of ACA on NF-kappaB and NF-kappaB-regulated gene expression activated by various carcinogens. We found that ACA suppressed NF-kappaB activation induced by a wide variety of inflammatory and carcinogenic agents, including TNF, IL-1beta, PMA, LPS, H(2)O(2), doxorubicin, and cigarette smoke condensate. Suppression was not cell type specific, because both inducible and constitutive NF-kappaB activations were blocked by ACA. ACA did not interfere with the binding of NF-kappaB to the DNA, but, rather, inhibited IkappaBalpha kinase activation, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, and subsequent p65 nuclear translocation. ACA also inhibited NF-kappaB-dependent reporter gene expression activated by TNF, TNFR1, TNFR-associated death domain protein, TNFR-associated factor-2, and IkappaBalpha kinase, but not that activated by p65. Consequently, ACA suppressed the expression of TNF-induced NF-kappaB-regulated proliferative (e.g., cyclin D1 and c-Myc), antiapoptotic (survivin, inhibitor of apoptosis protein-1 (IAP1), IAP2, X-chromosome-linked IAP, Bcl-2, Bcl-x(L), Bfl-1/A1, and FLIP), and metastatic (cyclooxygenase-2, ICAM-1, vascular endothelial growth factor, and matrix metalloprotease-9) gene products. ACA also enhanced the apoptosis induced by TNF and chemotherapeutic agents and suppressed invasion. Overall, our results indicate that ACA inhibits activation of NF-kappaB and NF-kappaB-regulated gene expression, which may explain the ability of ACA to enhance apoptosis and inhibit invasion.

Authors+Show Affiliations

Cytokine Research Section, Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, 77030, USA.No 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
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15905586

Citation

Ichikawa, Haruyo, et al. "Identification of a Novel Blocker of I Kappa B Alpha Kinase That Enhances Cellular Apoptosis and Inhibits Cellular Invasion Through Suppression of NF-kappa B-regulated Gene Products." Journal of Immunology (Baltimore, Md. : 1950), vol. 174, no. 11, 2005, pp. 7383-92.
Ichikawa H, Takada Y, Murakami A, et al. Identification of a novel blocker of I kappa B alpha kinase that enhances cellular apoptosis and inhibits cellular invasion through suppression of NF-kappa B-regulated gene products. J Immunol. 2005;174(11):7383-92.
Ichikawa, H., Takada, Y., Murakami, A., & Aggarwal, B. B. (2005). Identification of a novel blocker of I kappa B alpha kinase that enhances cellular apoptosis and inhibits cellular invasion through suppression of NF-kappa B-regulated gene products. Journal of Immunology (Baltimore, Md. : 1950), 174(11), 7383-92.
Ichikawa H, et al. Identification of a Novel Blocker of I Kappa B Alpha Kinase That Enhances Cellular Apoptosis and Inhibits Cellular Invasion Through Suppression of NF-kappa B-regulated Gene Products. J Immunol. 2005 Jun 1;174(11):7383-92. PubMed PMID: 15905586.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of a novel blocker of I kappa B alpha kinase that enhances cellular apoptosis and inhibits cellular invasion through suppression of NF-kappa B-regulated gene products. AU - Ichikawa,Haruyo, AU - Takada,Yasunari, AU - Murakami,Akira, AU - Aggarwal,Bharat B, PY - 2005/5/21/pubmed PY - 2005/8/9/medline PY - 2005/5/21/entrez SP - 7383 EP - 92 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J Immunol VL - 174 IS - 11 N2 - 1'-Acetoxychavicol acetate (ACA), extracted from rhizomes of the commonly used ethno-medicinal plant Languas galanga, has been found to suppress chemical- and virus-induced tumor initiation and promotion through a poorly understood mechanism. Because several genes that regulate cellular proliferation, carcinogenesis, metastasis, and survival are regulated by activation of the transcription factor NF-kappaB, we postulated that ACA might mediate its activity through modulation of NF-kappaB activation. For this report, we investigated the effect of ACA on NF-kappaB and NF-kappaB-regulated gene expression activated by various carcinogens. We found that ACA suppressed NF-kappaB activation induced by a wide variety of inflammatory and carcinogenic agents, including TNF, IL-1beta, PMA, LPS, H(2)O(2), doxorubicin, and cigarette smoke condensate. Suppression was not cell type specific, because both inducible and constitutive NF-kappaB activations were blocked by ACA. ACA did not interfere with the binding of NF-kappaB to the DNA, but, rather, inhibited IkappaBalpha kinase activation, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, and subsequent p65 nuclear translocation. ACA also inhibited NF-kappaB-dependent reporter gene expression activated by TNF, TNFR1, TNFR-associated death domain protein, TNFR-associated factor-2, and IkappaBalpha kinase, but not that activated by p65. Consequently, ACA suppressed the expression of TNF-induced NF-kappaB-regulated proliferative (e.g., cyclin D1 and c-Myc), antiapoptotic (survivin, inhibitor of apoptosis protein-1 (IAP1), IAP2, X-chromosome-linked IAP, Bcl-2, Bcl-x(L), Bfl-1/A1, and FLIP), and metastatic (cyclooxygenase-2, ICAM-1, vascular endothelial growth factor, and matrix metalloprotease-9) gene products. ACA also enhanced the apoptosis induced by TNF and chemotherapeutic agents and suppressed invasion. Overall, our results indicate that ACA inhibits activation of NF-kappaB and NF-kappaB-regulated gene expression, which may explain the ability of ACA to enhance apoptosis and inhibit invasion. SN - 0022-1767 UR - https://www.unboundmedicine.com/medline/citation/15905586/Identification_of_a_novel_blocker_of_I_kappa_B_alpha_kinase_that_enhances_cellular_apoptosis_and_inhibits_cellular_invasion_through_suppression_of_NF_kappa_B_regulated_gene_products_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=15905586 DB - PRIME DP - Unbound Medicine ER -