Study of the molecular mechanisms by which NSAIDs inhibit MMP-2 expression

• Main Authors: Mei-Ren Pan, 潘美仁
• Other Authors: Wen-Chun Hung
• Format: Others
• Language: zh-TW
• Published: 2002
• Online Access: http://ndltd.ncl.edu.tw/handle/78475204386312275894

碩士 === 高雄醫學大學 === 醫學研究所 === 90 === Human lung cancers are classified into four major categories : adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and small cell carcinoma based on their histological feature. Adenocarcinoma and squamous cell carcinoma are the most frequent ones(25-40%) followed by small cell lung cancer(20-25%), and large cell carcinoma. Cigarette smoking is the primary risk factor for lung cancer. Approximately 70% of lung cancer patients will die from metastatic disease. NSAIDs are among the most commonly used anti-inflammatory pharmaceutical compounds worldwide. NSAIDs have been shown to exhibit potent anti-metastatic and anti- angiogenic effect in vitro and in vivo. However, the mechanisms are still unclear. NSAIDs are cyclooxygenase(COX) inhibitors. Cyclooxygenase are the rate-limiting enzymes involved in conversion of arachidonic acid to Prostaglandins(PGs). Two COX isoforms have been described. COX-1 is constitutively expressed in almost cells and has characteristics of a housekeeping gene; COX-2 expression is induced by mitogens, cytokines or tumor promoters. Cyclooxygenase have been shown to promote matrix metalloproteinase-2 and -9 release in the hepatocytes. MMPs, a family of zinc-containing endoproteinase, were shown to be involved in angiogenesis and tumor metastasis. MMPs mediate selective proteolytic degradation of extracellular matrix, a essential process that is required angiogenesis. In this study, we investigate the effect of NSAIDs on the expression of MMPs. We found NSAIDs inhibit MMP-2, but not MMP-9, expression and activity via repression of transcription in lung cancer cells. However, the inhibitory effect of NS398 is not full dependent on inhibition of COX-2 because addition of PGE2 only partially reverse the action of NS398.It means that NS398 may inhibit MMP-2 expression via COX-dependent and COX-independent pathways. Promoter activity and EMSA assays show that NSAIDs reduce Sp1 DNA binding activity . Recent studies indicate that DNA binding activity of Sp1 can be regulated by post-translation modification( phosphorylation and glycosylation). So, we investigate the signaling pathway that mediates the effect of NSAIDs. We found NSAIDs inhibit MMP-2 via suppression of the ERK/Sp1-mediated transactivation and ERK activates MMP-2 expression and metastatic effecity via enhancement of Sp1 DNA binding and transactivation activity.