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.

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: Haruyo Ichikawa, Yasunari Takada, Akira Murakami, Bharat B Aggarwal
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 174 Issue 11 Pg. 7383-92 (Jun 01 2005) ISSN: 0022-1767 [Print] United States
• PMID: 15905586 (Publication Type: 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.)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antineoplastic Agents, Phytogenic
• Benzyl Alcohols
• DNA-Binding Proteins
• Growth Inhibitors
• Immunosuppressive Agents
• NF-kappa B
• Protein Kinase Inhibitors
• Terpenes
• Transcription Factor RelA
• Tumor Necrosis Factor-alpha
• Protein Serine-Threonine Kinases
• CHUK protein, human
• I-kappa B Kinase
• IKBKB protein, human
• IKBKE protein, human
• 1'-acetoxychavicol acetate

Topics

• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects, immunology)
• Benzyl Alcohols
• Cell Line, Tumor
• Cell Migration Inhibition
• Cell Movement (drug effects, immunology)
• Cell Proliferation (drug effects)
• DNA-Binding Proteins (antagonists & inhibitors, metabolism)
• Dose-Response Relationship, Drug
• Genes, Reporter (drug effects)
• Growth Inhibitors (pharmacology)
• Humans
• I-kappa B Kinase
• Immunosuppressive Agents (pharmacology)
• Jurkat Cells
• NF-kappa B (antagonists & inhibitors, genetics, metabolism, physiology)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Terpenes (pharmacology)
• Transcription Factor RelA
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, physiology)