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.
Huang
Wei-Chien
WC
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 10018, Taiwan.
Chan
Shu-Ting
ST
Yang
Tzu-Lin
TL
Tzeng
Cherng-Chyi
CC
Chen
Ching-Chow
CC
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects*; D051546:Cyclooxygenase 2; D024202:Electrophoretic Mobility Shift Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D051550:I-kappa B Kinase; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020298:U937 Cells / Q000187:drug effects / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases; D000097782:NF-kappaB-Inducing Kinase
D015107:4-Butyrolactone; D000897:Anti-Ulcer Agents; D051546:Cyclooxygenase 2; D051550:I-kappa B Kinase; D018799:Intercellular Adhesion Molecule-1; D007527:Isoenzymes; D008156:Luciferases; D020780:Matrix Metalloproteinase 9; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000097782:NF-kappaB-Inducing Kinase; C014096:alpha-methylene gamma-butyrolactone; C496540:PTGS2 protein, human; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human