Proteinase activated-receptor-2 induces cyclooxygenase-2 expression through beta-catenin and cyclic AMP response element binding protein

Chronic inflammation of mucosae is associated with an increased cancer risk. Tumorigenesis in these tissues is associated with the activity of some proteinases, cyclooxygenase (COX)-2 and -catenin. Serine proteinases participate in both inflammation and tumorigenesis through the activation of proteinase-activated receptor-2 (PAR2), which upregulates cyclooxygenase (COX)-2 by an unknown mechanism. We sought to determine if -catenin participated in PAR2-induced COX-2 expression, and through what cellular mechanism. In A549 epithelial cells, we showed that PAR2 activation increased COX-2 expression through the -catenin/Tcf transcription pathway. This effect was dependent upon ERK1/2 MAPkinase, which inhibited the -catenin regulating protein, GSK-3 and induced the activity of the cAMP response element binding protein, CREB. Knock-down of CREB by siRNA revealed that PAR2-induced -catenin transcriptional activity and COX-2 expression were CREB-dependent. Co-immunoprecipitation assay revealed a physical interaction between CREB and -catenin. Thus, PAR2 upregulated COX-2 expression via an ERK1/2-mediated activation of the -catenin/Tcf-4 and CREB pathways. These findings reveal new cellular mechanisms by which serine proteinases may participate in tumor development, and are particularly relevant to cancers associated with chronic mucosal inflammation, where serine proteinases are abundant and COX-2 overexpression is a common feature.