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Honokiol inhibits TNF-alpha-stimulated NF-kappaB activation and NF-kappaB-regulated gene expression through suppression of IKK activation.
Biochem Pharmacol. 2005 Nov 15; 70(10):1443-57.BP

Abstract

Honokiol, a small molecular weight lignan originally isolated from Magnolia officinalis, shows anti-angiogenic, anti-invasive and anti-proliferative activities in a variety of cancers. In this study, we investigated whether honokiol affects the transcription factor nuclear factor-kappa B (NF-kappaB) which controls a large number of genes involved in angiogenesis, metastasis and cell survival. We observed that the tumor necrosis factor-alpha (TNF-alpha)-induced NF-kappaB activation was blocked by honokiol in four different cancer cell lines as evidenced by EMSA. Honokiol did not directly affect the NF-kappaB-DNA binding. Immunoblot experiments demonstrated that honokiol inhibited the TNF-alpha-stimulated phosphorylation and degradation of the cytosolic NF-kappaB inhibitor IkappaBalpha. Furthermore, honokiol suppressed the intrinsic and TNF-alpha-stimulated upstream IkappaB kinases (IKKs) activities measured by a non-radioactive kinase assay using immunoprecipitated IKKs, suggesting a critical role of honokiol in abrogating the phosphorylation and degradation of IkappaBalpha. In a HeLa cell NF-kappaB-dependent luciferase reporter system, honokiol suppressed luciferase expression stimulated by TNF-alpha and by the transient transfection and expression of NIK (NF-kappaB-inducing kinase), wild type IKKbeta, constitutively active IKKalpha and IKKbeta, or the p65 subunit. Honokiol was also found to inhibit the nuclear translocation and phosphorylation of p65 subunit of NF-kappaB. RT-PCR results showed that honokiol suppressed NF-kappaB-regulated inflammatory and carcinogenic gene products including MMP-9, TNF-alpha, IL-8, ICAM-1 and MCP-1. In line with the observation that NF-kappaB activation may up-regulate anti-apoptotic genes, it was shown that honokiol enhanced TNF-alpha-induced apoptotic cell death. In summary, our results demonstrate that honokiol suppresses NF-kappaB activation and NF-kappaB-regulated gene expression through the inhibition of IKKs, which provides a possible mechanism for its anti-tumor actions.

Authors+Show Affiliations

Bioactive Products Research Group, Department of Biology and Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon Tong, Hong Kong SAR, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16181613

Citation

Tse, Anfernee Kai-Wing, et al. "Honokiol Inhibits TNF-alpha-stimulated NF-kappaB Activation and NF-kappaB-regulated Gene Expression Through Suppression of IKK Activation." Biochemical Pharmacology, vol. 70, no. 10, 2005, pp. 1443-57.
Tse AK, Wan CK, Shen XL, et al. Honokiol inhibits TNF-alpha-stimulated NF-kappaB activation and NF-kappaB-regulated gene expression through suppression of IKK activation. Biochem Pharmacol. 2005;70(10):1443-57.
Tse, A. K., Wan, C. K., Shen, X. L., Yang, M., & Fong, W. F. (2005). Honokiol inhibits TNF-alpha-stimulated NF-kappaB activation and NF-kappaB-regulated gene expression through suppression of IKK activation. Biochemical Pharmacology, 70(10), 1443-57.
Tse AK, et al. Honokiol Inhibits TNF-alpha-stimulated NF-kappaB Activation and NF-kappaB-regulated Gene Expression Through Suppression of IKK Activation. Biochem Pharmacol. 2005 Nov 15;70(10):1443-57. PubMed PMID: 16181613.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Honokiol inhibits TNF-alpha-stimulated NF-kappaB activation and NF-kappaB-regulated gene expression through suppression of IKK activation. AU - Tse,Anfernee Kai-Wing, AU - Wan,Chi-Keung, AU - Shen,Xiao-Ling, AU - Yang,Mengsu, AU - Fong,Wang-Fun, Y1 - 2005/09/21/ PY - 2005/06/21/received PY - 2005/08/08/revised PY - 2005/08/17/accepted PY - 2005/9/27/pubmed PY - 2005/12/24/medline PY - 2005/9/27/entrez SP - 1443 EP - 57 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 70 IS - 10 N2 - Honokiol, a small molecular weight lignan originally isolated from Magnolia officinalis, shows anti-angiogenic, anti-invasive and anti-proliferative activities in a variety of cancers. In this study, we investigated whether honokiol affects the transcription factor nuclear factor-kappa B (NF-kappaB) which controls a large number of genes involved in angiogenesis, metastasis and cell survival. We observed that the tumor necrosis factor-alpha (TNF-alpha)-induced NF-kappaB activation was blocked by honokiol in four different cancer cell lines as evidenced by EMSA. Honokiol did not directly affect the NF-kappaB-DNA binding. Immunoblot experiments demonstrated that honokiol inhibited the TNF-alpha-stimulated phosphorylation and degradation of the cytosolic NF-kappaB inhibitor IkappaBalpha. Furthermore, honokiol suppressed the intrinsic and TNF-alpha-stimulated upstream IkappaB kinases (IKKs) activities measured by a non-radioactive kinase assay using immunoprecipitated IKKs, suggesting a critical role of honokiol in abrogating the phosphorylation and degradation of IkappaBalpha. In a HeLa cell NF-kappaB-dependent luciferase reporter system, honokiol suppressed luciferase expression stimulated by TNF-alpha and by the transient transfection and expression of NIK (NF-kappaB-inducing kinase), wild type IKKbeta, constitutively active IKKalpha and IKKbeta, or the p65 subunit. Honokiol was also found to inhibit the nuclear translocation and phosphorylation of p65 subunit of NF-kappaB. RT-PCR results showed that honokiol suppressed NF-kappaB-regulated inflammatory and carcinogenic gene products including MMP-9, TNF-alpha, IL-8, ICAM-1 and MCP-1. In line with the observation that NF-kappaB activation may up-regulate anti-apoptotic genes, it was shown that honokiol enhanced TNF-alpha-induced apoptotic cell death. In summary, our results demonstrate that honokiol suppresses NF-kappaB activation and NF-kappaB-regulated gene expression through the inhibition of IKKs, which provides a possible mechanism for its anti-tumor actions. SN - 0006-2952 UR - https://www.unboundmedicine.com/medline/citation/16181613/Honokiol_inhibits_TNF_alpha_stimulated_NF_kappaB_activation_and_NF_kappaB_regulated_gene_expression_through_suppression_of_IKK_activation_ DB - PRIME DP - Unbound Medicine ER -