Journal Article

Inhibition of ICAM-1 gene expression, monocyte adhesion and cancer cell invasion by targeting IKK complex: molecular and functional study of novel α-methylene-γ-butyrolactone derivatives

Wei-Chien Huang, Shu-Ting Chan, Tzu-Lin Yang, Cherng-Chyi Tzeng and Ching-Chow Chen

in Carcinogenesis

Volume 25, issue 10, pages 1925-1934
Published in print October 2004 | ISSN: 0143-3334
Published online October 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh211
Inhibition of ICAM-1 gene expression, monocyte adhesion and cancer cell invasion by targeting IKK complex: molecular and functional study of novel α-methylene-γ-butyrolactone derivatives

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The transcription factor nuclear factor-kappaB (NF-κB) is a regulator related to cellular inflammation, immune responses and carcinogenesis. Therefore, components of the NF-κB-activating singnaling pathways are frequent targets for the anti-inflammatory and anticancer agents. In this study, CYL-19 s and CYL-26z, two synthetic α-methylene-γ-butyrolactone derivatives, were shown to inhibit the tumor necrosis factor-alpha (TNF-α)-induced intercellular adhesion molecule-1 (ICAM-1) expression in human A549 alveolar epithelial cells and the adhesion of U937 cells to these cells. RT–PCR analysis also demonstrated their inhibitory effects on TNF-α-induced ICAM-1 mRNA expression. TNF-α-induced ICAM-1 and NF-κB-dependent promoter activities were attenuated by CYL-19 s and CYL-26z. ICAM-1 promoter activities induced by the over-expression of wild-type NF-κB-inducing kinase and IκB kinase β (IKKβ) were also inhibited by both compounds. Furthermore, CYL-19 s and CYL-26z inhibited the TNF-α-induced phosphorylation and degradation of IκBα and NF-κB-specific DNA–protein binding activity via targeting IKK complex directly, without any effect on the activations of other kinases such as ERK1/2 and p38. In addition to ICAM-1 expression, CYL-19 s and CYL-26z also suppressed other NF-κB-mediated gene expressions such as matrix metalloproteinase-9 (MMP-9) mRNA and cyclooxygnease-2 (COX-2) protein. In Matrigel assays, ICAM-1 and COX-2 expressions induced by TNF-α elicited A549 and NCI-H292 cell invasion, respectively, and these effects were inhibited by both compounds. In summary, our data demonstrated that CYL-19 s and CYL-26z down-regulate the TNF-α-induced inflammatory genes expression through suppression of IKK activity and NF-κB activation. These agents may be effective in the anti-inflammatory and anticancer therapy.

Keywords: COX-2, cyclooxygenase-2; DMEM, Dulbecco's modified Eagle's medium; FCS, fetal calf serum; ICAM-1, intercellular adhesion molecule-1; IκB, inhibitor of NF-κB; IKK, IκB kinase; MMP-9, matrix metalloproteinase-9; NF-κB, nuclear factor-kappaB; NIK, NF-κB-inducing kinase; TNF-α, tumor necrosis factor-alpha

Journal Article.  7156 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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