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Research ArticleArticle

Embelin, an Inhibitor of X Chromosome-Linked Inhibitor-of-Apoptosis Protein, Blocks Nuclear Factor-κB (NF-κB) Signaling Pathway Leading to Suppression of NF-κB-Regulated Antiapoptotic and Metastatic Gene Products

Kwang Seok Ahn, Gautam Sethi and Bharat B. Aggarwal
Molecular Pharmacology January 2007, 71 (1) 209-219; DOI: https://doi.org/10.1124/mol.106.028787
Kwang Seok Ahn
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Gautam Sethi
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Bharat B. Aggarwal
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Abstract

Identifying the active chemical ingredients of ancient medicines and the molecular targets of those ingredients is an attractive therapeutic objective. Embelin, identified primarily from the Embelia ribes plant, is one such compound shown to exhibit chemopreventive, anti-inflammatory, and apoptotic activities through an unknown mechanism. Because nuclear factor-κB (NF-κB) regulates several genes associated with inflammation, proliferation, carcinogenesis, and apoptosis, we postulated that embelin might mediate its activity through modulation of NF-κB activation. We found that embelin inhibited tumor necrosis factor (TNF) α-induced NF-κB activation. Both inducible and constitutive NF-κB activation were abrogated by embelin. In addition, NF-κB activated by diverse stimuli such as interleukin-1β, lipopolysaccharide, phorbol myristate acetate, okadaic acid, hydrogen peroxide, and cigarette smoke condensate also was suppressed. We found that embelin inhibited sequentially the TNFα-induced activation of the inhibitory subunit of NF-κBα (IκBα) kinase, IκBα phosphorylation, IκBα degradation, and p65 phosphorylation and nuclear translocation. Embelin also suppressed NF-κB-dependent reporter gene transcription induced by TNFα, TNF receptor-1 (TNFR1), TNFR1-associated death domain protein, TNFR-associated factor-2, NF-κB-inducing kinase, and IκBα kinase but not by p65. Furthermore, we found that embelin down-regulated gene products involved in cell survival, proliferation, invasion, and metastasis of the tumor. This down-regulation was associated with enhanced apoptosis by cytokine and chemotherapeutic agents. Together, our results indicate that embelin is a novel NF-κB blocker and potential suppressor of tumorigenesis.

Footnotes

  • This work was supported by a grant from the Clayton Foundation for Research (to B.B.A.), National Institutes of Health grant P01-CA91844 on lung chemoprevention (to B.B.A.), and National Institutes of Health Head and Neck Specialized Programs in Research Excellence grant P50-CA97007 (to B.B.A.).

  • ABBREVIATIONS: RIP, receptor-interacting protein; XIAP, X chromosome-linked inhibitor-of-apoptosis protein; TNFα, tumor necrosis factorα; NF-κB, nuclear factor-κB; CSC, cigarette smoke condensate; FBS, fetal bovine serum; PMA, phorbol 12-myristate 13-acetate; OA, okadaic acid; LPS, lipopolysaccharide; IL, interleukin; IκBα, inhibitory subunit of NF-κBα; MMP, matrix metalloproteinase; PARP, poly(ADP-ribose) polymerase; IAP1, inhibitor-of-apoptosis protein 1; TRAF, tumor necrosis factor receptor-associated factor; VEGF, vascular endothelial growth factor; ICAM-1, intercellular adhesion molecule 1; COX, cyclooxygenase; IKK, IκBα kinase; cFLIP, complementary Fas-associated death domain protein-like interleukin-1β-converting enzyme-inhibitory protein; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; PAGE, polyacrylamide gel electrophoresis; EMSA, electrophoretic mobility shift assay; SEAP, secretory alkaline phosphatase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; TNFR, tumor necrosis factor receptor; TRADD, tumor necrosis factor receptor 1-associated death domain protein; NIK, NF-κB-inducing kinase; MEKK, mitogen-activated protein kinase kinase kinase; TAK, transforming growth factor-β-activated kinase.

    • Received July 12, 2006.
    • Accepted October 5, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (1)
Molecular Pharmacology
Vol. 71, Issue 1
1 Jan 2007
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Research ArticleArticle

Embelin, an Inhibitor of X Chromosome-Linked Inhibitor-of-Apoptosis Protein, Blocks Nuclear Factor-κB (NF-κB) Signaling Pathway Leading to Suppression of NF-κB-Regulated Antiapoptotic and Metastatic Gene Products

Kwang Seok Ahn, Gautam Sethi and Bharat B. Aggarwal
Molecular Pharmacology January 1, 2007, 71 (1) 209-219; DOI: https://doi.org/10.1124/mol.106.028787

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Research ArticleArticle

Embelin, an Inhibitor of X Chromosome-Linked Inhibitor-of-Apoptosis Protein, Blocks Nuclear Factor-κB (NF-κB) Signaling Pathway Leading to Suppression of NF-κB-Regulated Antiapoptotic and Metastatic Gene Products

Kwang Seok Ahn, Gautam Sethi and Bharat B. Aggarwal
Molecular Pharmacology January 1, 2007, 71 (1) 209-219; DOI: https://doi.org/10.1124/mol.106.028787
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