Proteinase‐activated receptor (PAR)‐2 stimulates cyclooxygenase‐2 (COX‐2) expression in Caco‐2 colon cancer cells: role of matrix metalloproteinases (MMPs)

Abstract

Colon cancer is associated with elevated levels of trypsin, an activator of PAR2; PAR2 activation stimulates MMP‐9 release and COX‐2 expression, which are both involved in inflammation and cancer. We hypothesize that MMPs participate in PAR2‐induced COX‐2 expression in Caco‐2 colon cancer cells. Cells were treated for 3hr with PAR2#‐activating peptide (fLI) with or without a pan‐MMP inhibitor. Concentrated, conditioned media from treated cells were used to treat separate cells. Other cells were treated directly with activated MMP‐9 or tissue inhibitor of metalloproteinase (TIMP)‐1, an endogenous MMP inhibitor with greater selectivity for MMP‐9. COX‐2 expression was assessed by western blot. Secreted MMPs were analyzed by zymography. The pan‐MMP inhibitor decreased fLI‐induced COX‐2 expression in Caco‐2 cells. Concentrated, conditioned media from fLI‐treated cells induced COX‐2 expression in separate cells. TIMP‐1 did not suppress PAR2‐induced COX‐2 expression nor did direct treatment with MMP‐9 increase its expression. Caco‐2 cells secrete gelatinases and casein‐degrading MMPs. It is unclear yet whether PAR2 activation alters the secreted MMP profile. In summary, PAR2 activation stimulates COX‐2 expression via a MMP other than MMP‐9 in Caco‐2 cells. Understanding this pathway may help define molecules to target in the progression from inflammation to cancer. Funded by CAG/CIHR/Abbott.