Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to exert anti-angiogenic and anti-metastatic activity both in vitro and in vivo. Block of angiogenesis and metastasis by NSAIDs has been found to be mediated partly via suppression of matrix metalloproteinase (MMP) activity. However, the molecular mechanism of this inhibitory action has not been well defined. Recent works demonstrated that a membrane-anchored MMP inhibitor RECK may potently suppress MMP-2 and -9 activity to inhibit angiogenesis and metastasis in vitro and in vivo. In this study, we test the possibility that NSAIDs may up-regulate RECK to inhibit MMP activity. RT-PCR analyses showed that NS398 and aspirin up-regulated RECK mRNA level in CL-1 human lung cancer cells. Additionally, NSAIDs increased RECK protein level as detected by immunoblotting. Since RECK is a membrane-anchored glycoprotein, we also performed immunofluorescent staining to assess the expression of RECK on cell surface. Our results showed that fluorescent intensity of RECK was obviously increased after NSAID treatment. Moreover, induction of RECK by NSAIDs was associated with reduction of MMP-2 activity. We also found that NSAID-activated RECK expression might not be mediated via inhibition of cyclo-oxygenases (COXs) because addition of prostaglandin E(2) (PGE(2)) could not counteract the effect of NSAIDs and overexpression of COX-2 could not down-regulate RECK. Taken together, our results suggest that induction of RECK expression may be one of the mechanisms by which NSAIDs suppress MMP activity to block angiogenesis and metastasis.