Non‐steroidal anti‐inflammatory drugs inhibit matrix metalloproteinase‐2 expression via repression of transcription in lung cancer cells

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Abstract
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.