Proteinase-activated Receptor-2 Induces Cyclooxygenase-2 Expression through β-Catenin and Cyclic AMP-response Element-binding Protein*
- Hongying Wang‡,1,
- Shoubin Wen‡,
- Nigel W. Bunnett§,
- Richard Leduc¶,
- Morley D. Hollenberg‡∥ and
- Wallace K. MacNaughton‡,**,2
- ‡Inflammation Research Network and the Departments of **Physiology and Biophysics and ∥Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta T2N 4N1, Canada, the §Department of Surgery and Physiology, University of California, San Francisco, California 94143-0104, and the ¶University of Sherbrooke, Sherbrooke, Quebec J1K 2R1, Canada
- ↵2 Senior Scholar of the Alberta Heritage Foundation for Medical Research. To whom correspondence should be addressed: Dept. of Physiology and Biophysics, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta T2N 4N1, Canada. Tel.: 403-220-5882; Fax: 403-283-3840; E-mail: wmacnaug{at}ucalgary.ca.
Abstract
Chronic inflammation of mucosae is associated with an increased cancer risk. Tumorigenesis in these tissues is associated with the activity of some proteinases, cyclooxygenase-2 (COX-2), and β-catenin. Serine proteinases participate in both inflammation and tumorigenesis through the activation of proteinase-activated receptor-2 (PAR2), which up-regulates COX-2 by an unknown mechanism. We sought to determine whether β-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 β-catenin/T cell factor transcription pathway. This effect was dependent upon ERK1/2 MAPK, which inhibited the β-catenin-regulating protein, glycogen synthase kinase-3β, and induced the activity of the cAMP-response element-binding protein (CREB). Knockdown of CREB by small interfering RNA revealed that PAR2-induced β-catenin transcriptional activity and COX-2 expression were CREB-dependent. A co-immunoprecipitation assay revealed a physical interaction between CREB and β-catenin. Thus, PAR2 up-regulated COX-2 expression via an ERK1/2-mediated activation of the β-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.
- Received April 10, 2007.
- Revision received October 5, 2007.
- The American Society for Biochemistry and Molecular Biology, Inc.
