Arachidonic acid is metabolized to prostaglandin H₂ by cyclooxygenase (COX). Prostaglandins exert diverse physiological actions to maintain mucosal integrity, regulation of secretion and motility. Among the various COX products, abnormally elevated levels of prostaglandin E₂ (PGE₂) have been often observed in various types of human cancers. Moreover, COX-2, the inducible COX isozyme, has been implicated in pathogenesis of various malignancies. PGE₂ generated by COX-2 increased the cellular cAMP level via EP2, a cell-surface receptor of this prostaglandin, and further stimulates expression of COX-2. PGE₂ activates the epidermal growth factor receptor-hepatocyte growth factor receptor-β-catenin-uPAR signaling pathway, thereby augmenting invasiveness and metastasis of cancer cells. In contrast, 15-deoxy-Δ^12,14PGJ₂ (15d-PGJ₂), another COX-2 metabolite and a natural ligand for the peroxisome proliferator-activated receptors γ (PPARγ), causes apoptosis, inhibition of cell growth, anti-inflammation, and cytoprotection. 15d-PGJ₂ and some synthetic PPARγ ligands also regulate the expression of COX-2 through peroxisome proliferator response element, which is accompanied by induction of apoptosis. Therefore, the physiological and toxicological effects associated with induction of COX-2 expression depend on types of cells and stimuli.

Keywords: Cyclooxygenase-2, 15-deoxy-Δ^12,14prostaglandin J₂, PGE_2, Cell growth/ death, Peroxisome proliferator-activated receptor γ ligands