Inhibition of ICAM-1 gene expression, monocyte adhesion and cancer cell invasion by targeting IKK complex: molecular and functional study of novel alpha-methylene-gamma-butyrolactone derivatives.
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.
Mesh Terms:
4-Butyrolactone, Anti-Ulcer Agents, Cell Adhesion, Cyclooxygenase 2, Electrophoretic Mobility Shift Assay, Epithelial Cells, Gene Expression Regulation, Humans, I-kappa B Kinase, Intercellular Adhesion Molecule-1, Isoenzymes, Luciferases, Matrix Metalloproteinase 9, Membrane Proteins, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Monocytes, NF-kappa B, Neoplasm Invasiveness, Phosphorylation, Promoter Regions, Genetic, Prostaglandin-Endoperoxide Synthases, Protein-Serine-Threonine Kinases, Reverse Transcriptase Polymerase Chain Reaction, Tumor Necrosis Factor-alpha, U937 Cells, p38 Mitogen-Activated Protein Kinases
4-Butyrolactone, Anti-Ulcer Agents, Cell Adhesion, Cyclooxygenase 2, Electrophoretic Mobility Shift Assay, Epithelial Cells, Gene Expression Regulation, Humans, I-kappa B Kinase, Intercellular Adhesion Molecule-1, Isoenzymes, Luciferases, Matrix Metalloproteinase 9, Membrane Proteins, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Monocytes, NF-kappa B, Neoplasm Invasiveness, Phosphorylation, Promoter Regions, Genetic, Prostaglandin-Endoperoxide Synthases, Protein-Serine-Threonine Kinases, Reverse Transcriptase Polymerase Chain Reaction, Tumor Necrosis Factor-alpha, U937 Cells, p38 Mitogen-Activated Protein Kinases
Carcinogenesis
Date: Oct. 01, 2004
PubMed ID: 15217903
View in: Pubmed Google Scholar
Download Curated Data For This Publication
187636
Switch View:
- Interactions 1