Cyclo‐oxygenase‐2 Plays a Critical Role in UV‐induced Skin Carcinogenesis†

Abstract

Besides induction of DNA damage and p53 mutations, chronic exposure to UV irradiation leads to the constitutive up‐regulation of cyclo‐oxygenase‐2 (COX‐2) expression and to increased production of its primary product in skin, prostaglandin E 2 (PGE 2). COX‐2 has also been shown to be constitutively overexpressed in mouse, as well as human, UV‐induced skin cancers and premalignant lesions. UV exposure results in ligand‐independent activation of the epidermal growth factor receptor and subsequent activation of mitogen‐activated protein kinase and phosphatidylinositol 3‐kinase/Akt pathways leading to transcriptional activation of the COX‐2 gene. Use of COX‐2‐specific inhibitors and genetic manipulation of COX‐2 expression have demonstrated that UV induction of COX‐2 in the skin contributes to the induction of epidermal hyperplasia, edema, inflammation, and counters the induction of apoptosis after UV exposure. Likewise, inhibition of COX‐2 activity or reduced expression in COX‐2 knockout mice resulted in significantly reduced UV‐induced tumorigenesis, while overexpression of COX‐2 in transgenic mice enhanced UV‐induced tumor development. A combination of signaling from the PGE 2 EP1, EP2 and/or EP4 receptors mediates the effects of COX‐2 overexpression. These studies demonstrate the crucial role of COX‐2 in the development of UV‐related nonmelanoma skin cancers.