Inhibition of ICAM-1 gene expression, monocyte adhesion and cancer cell invasion by targetin IKK complex: Molecular and functional study of novel α-methylene-γ-butyrolactone derivatives
Journal
Carcinogenesis
Journal Volume
25
Journal Issue
10
Pages
1925-1934
Date Issued
2004
Author(s)
Abstract
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-19s and CYL-26z, two synthetic α-methylene-γ-butyrolactone derivatives, were shown to inhibit the tumor necrosis factor-alpha (TNF-γ)-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-κ B-dependent promoter activities were attenuated by CYL-19s 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-19s 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-19s and CYL-26z also suppressed other NF-κ B-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-19s 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. ? Oxford University Press 2004; all rights reserved.
SDGs
Other Subjects
antiinflammatory agent; antineoplastic agent; cyclooxygenase 2; cyl 19s; cyl 26z; gamma butyrolactone derivative; gelatinase B; I kappa B alpha; I kappa B kinase; immunoglobulin enhancer binding protein; intercellular adhesion molecule 1; messenger RNA; mitogen activated protein kinase 1; mitogen activated protein kinase p38; phosphotransferase; tumor necrosis factor alpha; unclassified drug; antiinflammatory activity; antineoplastic activity; article; cancer cell; cancer invasion; cell adhesion; cell assay; cell line; cell strain U937; complex formation; controlled study; down regulation; drug efficacy; drug structure; drug targeting; enzyme activation; enzyme inhibition; epithelium cell; gene activity; gene expression; gene induction; gene overexpression; gene repression; human; human cell; immunoregulation; lung alveolus epithelium; molecular biology; monocyte; priority journal; promoter region; protein degradation; protein DNA binding; protein phosphorylation; reverse transcription polymerase chain reaction; wild type; 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; Neoplasm Invasiveness; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Promoter Regions (Genetics); Prostaglandin-Endoperoxide Synthases; Protein-Serine-Threonine Kinases; Reverse Transcriptase Polymerase Chain Reaction; Tumor Necrosis Factor-alpha; U937 Cells
Type
journal article