Non-steroidal anti-inflammatory drugs reactivate SPARC expression via promoter demethylation in human lung cancer cells to inhibit cell invasion

B11

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to exhibit potential anti-metastatic and anti-angiogeneic effect in vivo and in vitro. One of the mechanisms by which NSAIDs suppress tumorigenesis is inhibition of angiogenesis and metastasis. In this study, we used microarray system to study the change of expression profile of metastasis-related genes regulated by NS398, a NSAID and cyclooxygenase-2 (COX-2) inhibitor. We found that several negative regulators of cell invasion including secreted protein acidic and rich in cycteine (SPARC), thrombospondin 1 (TSP1), thrombospondin 3 (TSP3) and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) are up-regulated by NS398. Functional assay indicated that SPARC is a critical mediator for NSAIDs to inhibit cell invasion. More importantly, we demonstrated that up-regulation of SPARC expression in human lung cancer cells is mediated via inhibition of DNA methyltransferase (DNMT) expression and promoter demethylation. This is the first report to show that NSAIDs may inhibit the expression of DNMT 1 and 3b to reverse promoter methylation and to reactivate the expression of tumor suppressor genes such as SPARC in cancer cells to inhibit cell invasion. Our results provide new insights for the understanding of the anti-cancer actions of NSAIDs.