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Identification of a Novel Blocker of IB Kinase That Enhances Cellular Apoptosis and Inhibits Cellular Invasion through Suppression of NF-B-Regulated Gene Products¹

Haruyo Ichikawa^*, Yasunari Takada^*, Akira Murakami and Bharat B. Aggarwal^2,*

^* Cytokine Research Section, Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030; and Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan

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-B, we postulated that ACA might mediate its activity through modulation of NF-B activation. For this report, we investigated the effect of ACA on NF-B and NF-B-regulated gene expression activated by various carcinogens. We found that ACA suppressed NF-B activation induced by a wide variety of inflammatory and carcinogenic agents, including TNF, IL-1, PMA, LPS, H₂O₂, doxorubicin, and cigarette smoke condensate. Suppression was not cell type specific, because both inducible and constitutive NF-B activations were blocked by ACA. ACA did not interfere with the binding of NF-B to the DNA, but, rather, inhibited IB kinase activation, IB phosphorylation, IB degradation, p65 phosphorylation, and subsequent p65 nuclear translocation. ACA also inhibited NF-B-dependent reporter gene expression activated by TNF, TNFR1, TNFR-associated death domain protein, TNFR-associated factor-2, and IB kinase, but not that activated by p65. Consequently, ACA suppressed the expression of TNF-induced NF-B-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-B and NF-B-regulated gene expression, which may explain the ability of ACA to enhance apoptosis and inhibit invasion.

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