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
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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DOI：
10.1093/carcin/bgh211
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发表时间：
2004-10-01
期刊：
影响因子：
4.7
通讯作者：
Chen, CC
中科院分区：
文献类型：
--
作者：
Huang, WC;Chan, ST;Chen, CC
The transcription factor nuclear factor-kappaB (NF-kappaB) is a regulator related to cellular inflammation, immune responses and carcinogenesis. Therefore, components of the NF-kappaB-activating singnaling pathways are frequent targets for the anti-inflammatory and anticancer agents. In this study, CYL-19 s and CYL-26z, two synthetic alpha-methylene-gamma-butyrolactone derivatives, were shown to inhibit the tumor necrosis factor-alpha (TNF-alpha)-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-alpha-induced ICAM-1 mRNA expression. TNF-alpha-induced ICAM-1 and NF-kappaB-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-kappaB-inducing kinase and IkappaB kinase beta (IKKbeta) were also inhibited by both compounds. Furthermore, CYL-19 s and CYL-26z inhibited the TNF-alpha-induced phosphorylation and degradation of IkappaBalpha and NF-kappaB-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-kappaB-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-alpha 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-alpha-induced inflammatory genes expression through suppression of IKK activity and NF-kappaB activation. These agents may be effective in the anti-inflammatory and anticancer therapy.
