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Experimental Biology and Medicine 233:456-462 (2008)
doi: 10.3181/0709-RM-257
© 2008 Society for Experimental Biology and Medicine

ORIGINAL RESEARCH ARTICLE

The Nonsteroidal Anti-Inflammatory Drug NS398 Reactivates SPARC Expression via Promoter Demethylation to Attenuate Invasiveness of Lung Cancer Cells

Mei-Ren Pan*, Hui-Chiu Chang*, Lea-Yea Chuang{dagger} and Wen-Chun Hung{ddagger},§,||,1

* Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; {dagger} Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; {ddagger} Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan; § Center for Gene Regulation and Signal Transduction Research, National Cheng-Kung University, Kaohsiung, Taiwan; and || National Sun Yat-Sen University-Kaohsiung Medical University Joint Research Center, Kaohsiung, Taiwan

To whom requests for reprints should be addressed at 1 Institute of Biomedical Sciences, National Sun Yat-Sen University, No.70, Lien-Hai Road, Kaohsiung 804, Taiwan. E-mail: hung1228{at}ms10.hinet.net

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.

Key Words: nonsteroidal anti-inflammatory drugs • cyclooxygenase-2 • SPARC • promoter • methylation


Related articles in EBM:

NSAIDs: Painkillers, Inflammation Inhibitors, Anti-Cancer Drugs and New Demethylating Agents

EBM 2008 233: xii. [Full Text]  





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