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.
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.
Ichikawa
Haruyo
H
Cytokine Research Section, Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, 77030, USA.
Takada
Yasunari
Y
Murakami
Akira
A
Aggarwal
Bharat B
BB
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D001592:Benzyl Alcohols; D045744:Cell Line, Tumor; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019169:Jurkat Cells; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology*; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000972:Antineoplastic Agents, Phytogenic; D001592:Benzyl Alcohols; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D013729:Terpenes; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C047948:1'-acetoxychavicol acetate