This paper is part of a special issue dedicated to Professor Hasan Mukhtar on the occasion of his 60th birthday.
Cyclo-oxygenase-2 Plays a Critical Role in UV-induced Skin Carcinogenesis†
Article first published online: 11 JAN 2008
© 2008 The Authors
Photochemistry and Photobiology
Volume 84, Issue 2, pages 322–329, March/April 2008
How to Cite
Rundhaug, J. E. and Fischer, S. M. (2008), Cyclo-oxygenase-2 Plays a Critical Role in UV-induced Skin Carcinogenesis. Photochemistry and Photobiology, 84: 322–329. doi: 10.1111/j.1751-1097.2007.00261.x
- Issue published online: 11 JAN 2008
- Article first published online: 11 JAN 2008
- Received 28 September 2007, accepted 5 November 2007
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 E2 (PGE2). 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 PGE2 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.