Prostaglandin E ₂ enhances intestinal adenoma growth via activation of the ras-mitogen-activated protein kinase cascade

A large body of clinical, genetic, and biochemical evidence indicates that cyclooxygenase-2 (COX-2), a key enzyme for prostanoid biosynthesis, contributes to the promotion of colorectal cancer. COX-2-derived prostaglandin E ₂ (PGE ₂) is the most abundant prostaglandin found in several gastrointestinal malignancies. Although PGE ₂ enhances intestinal adenoma growth in Apc ^min mice, the mechanism(s) by which it accelerates tumor growth is not completely understood. Here we investigated how PGE ₂ promotes intestinal tumor growth and the signaling pathways responsible for its effects. We observed that PGE ₂ treatment leads to increased epithelial cell proliferation and induces COX-2 expression in intestinal adenomas. Furthermore, we show that PGE ₂ regulation of COX-2 expression is mediated by activation of a Ras-mitogen-activated protein kinase signaling cascade. One intriguing finding is that COX-2-derived PGE ₂ mimics the effects of constitutively active Ras through a self amplifying loop that allows for a distinct growth advantage.