title: The nonsteroidal anti-inflammatory drug NS398 reactivates SPARC expression via promoter demethylation to attenuate invasiveness of lung cancer cells.
abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to exhibit potent anticancer effects in vitro and in vivo. One of the mechanisms by which NSAIDs suppress tumorigenesis is inhibition of angiogenesis and metastasis. In this study, we used a microarray system to study the change of expression profile of metastasis-related genes regulated by NS398, a NSAID and a cyclooxygenase-2 (COX-2) inhibitor. We found that several negative regulators of cell invasion, including secreted protein acidic and rich in cysteine (SPARC), thrombospondin 1 (TSP-1), thrombospondin 3 (TSP-3), and tissue inhibitors of matrix metalloproteinase-2 (TIMP-2) are upregulated by NS398. In addition, we demonstrated that upregulation of SPARC expression by NS398 in human lung cancer cells is mediated by promoter demethylation and associated with a decrease in DNA methyltransferase (DNMT) expression. This is the first report to show that NS398 can inhibit the expression of DNMT1 and 3b. Functional assay indicated that SPARC is a critical mediator for NS398 to inhibit cell invasion. Our results provide new insights for the understanding of the anticancer actions of NSAIDs.
authors: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Mei-Ren
authors: MR
authors: Pan
authors: Hui-Chiu
authors: HC
authors: Chang
authors: Lea-Yea
authors: LY
authors: Chuang
authors: Wen-Chun
authors: WC
authors: Hung
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009578:Nitrobenzenes / Q000378:metabolism* / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D015676:Osteonectin / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D013449:Sulfonamides / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007527:Isoenzymes; D009578:Nitrobenzenes; D015676:Osteonectin; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D004248:DNA (Cytosine-5-)-Methyltransferases