Induction of cyclooxygenase-2 expression by prostaglandin E₂ stimulation of the prostanoid EP4 receptor via coupling to G_αi and transactivation of the epidermal growth factor receptor in HCA-7 human colon cancer cells

Increased expressions of cyclooxygenase-2 (COX-2) and its downstream metabolite, prostaglandin E₂ (PGE₂), are well documented events in the development of colorectal cancer. Interestingly, PGE₂ itself can induce the expression of COX-2 thereby creating the potential for positive feedback. Although evidence for such a positive feedback has been previously described, the specific E-type prostanoid (EP) receptor subtype that mediates this response, as well as the relevant signaling pathways, remain unclear. We now report that the PGE₂ stimulated induction of COX-2 expression in human colon cancer HCA-7 cells is mediated by activation of the prostanoid EP4 receptor subtype and is followed by coupling of the receptor to G_αi and the activation of phosphatidylinositol 3-kinase. Subsequent activation of metalloproteinases releases membrane bound heparin-binding epidermal growth factor-like growth factor resulting in the transactivation of epidermal growth factor receptors and the activation of the extracellular signal-regulated kinases and induction of COX-2 expression. This induction of COX-2 expression by PGE₂ stimulation of the prostanoid EP4 receptor may underlie the upregulation of COX-2 during colorectal cancer and appears to be an early event in the process of tumorigenesis.