Non-steroidal anti-inflammatory drugs inhibit matrix metalloproteinase-2 expression via repression of transcription in lung cancer cells.
Recent studies show that up-regulation of cyclooxygenase-2 (COX-2) in human cancer cells induces activation of matrix metalloproteinases (MMPs) and increase of metastatic potential. In this study, we investigate the effect of a COX-2 selective inhibitor, NS398, on the expression and enzymatic activity of MMPs in human lung cancer cells. We found that NS398 inhibited MMP-2, not MMP-9, mRNA expression. NS398 also reduced the amount of MMP-2, not MMP-9, released into the medium. Additionally, this COX-2 inhibitor attenuated the degrading activity of MMP-2 as demonstrated by gelatin zymography. Investigation of cellular MMP-2 by Western blotting indicated that synthesis and processing of MMP-2 was significantly suppressed by NS398. We performed promoter activity assay to address whether NS398 might affect MMP-2 gene transcription. Our results indicated that NS398 directly inhibited MMP-2 promoter activity. However, the inhibitory effect of NS398 is not fully dependent on inhibition of COX-2 because a high concentration of NS398 was needed to suppress MMP-2 expression and addition of prostaglandin E2 only partially reversed the action of NS398. Moreover, a non-selective COX inhibitor indomethacin also suppressed the expression of MMP-2. Taken together, these results indicate that non-steroidal anti-inflammatory drugs suppress MMP-2 expression via repression of transcription and support the notion that COX inhibitors may be useful in inhibition and/or prevention of metastasis.
Pan
M R
MR
Institute of Medicine, Kaohsiung Medical University, Taiwan.
Chuang
L Y
LY
Hung
W C
WC
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017077:Culture Media, Conditioned; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D009578:Nitrobenzenes / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D017077:Culture Media, Conditioned; D016861:Cyclooxygenase Inhibitors; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone