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 in crease of metastatic potential. In this study, we investigate the effect of a COX-2 selective inhibitor, NS398, on the expression and enzymatic activi ty 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 MM P-9, released into the medium. Additionally, this COX-2 inhibitor attenuate d the degrading activity of MMP-2 as demonstrated by gelatin zymography. In vestigation 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 t ranscription. Our results indicated that NS398 directly inhibited MMP-2 pro moter activity. However, the inhibitory effect of NS398 is not fully depend ent on inhibition of COX-2 because a high concentration of NS398 was needed to suppress MMP-2 expression and addition of prostaglandin E-2 only partia lly reversed the action of NS398. Moreover, a nonselective COX inhibitor in domethacin also suppressed the expression of MMP-2. Taken together, these r esults indicate that non-steroidal anti-inflammatory drugs suppress MMP-2 e xpression via repression of transcription and support the notion that COX i nhibitors may be useful in inhibition and/or prevention of metastasis. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Sc ience B.V. All rights reserved.