A role for cyclooxygenase-2 in ultraviolet light-induced skin carcinogenesis.
Nonmelanoma skin cancer is the most prevalent cancer in the United States and its incidence is on the rise. These cancers generally arise on sun-exposed areas of the body and the ultraviolet (UV) B spectrum of sunlight has been clearly identified as the major carcinogen responsible for skin cancer development. Besides inducing DNA damage directly, UV exposure of the skin induces the expression of the enzyme cyclooxygenase-2 (COX-2), which catalyzes the first step in the conversion of arachidonic acid to prostaglandins, the primary product in skin being prostaglandin E(2) (PGE(2)). COX-2 has been shown to be overexpressed in premalignant lesions as well as in nonmelanoma skin cancers in both humans and mice chronically exposed to UV. Through the use of COX-2-selective inhibitors and COX-2 knockout mice, it has been shown that UV-induced COX-2 expression plays a major role in UV-induced PGE(2) production, inflammation, edema, keratinocyte proliferation, epidermal hyperplasia, and generation of a pro-oxidant state leading to oxidative DNA damage. Chronic exposure to UV leads to chronic up-regulation of COX-2 expression and chronic inflammation along with the accumulation of DNA damage and mutations, all of which combine to induce malignant changes in epidermal keratinocytes and skin cancers. Both inhibition of COX-2 activity and reduction in COX-2 expression by genetic manipulations significantly reduce, while overexpression of COX-2 in transgenic mice significantly increases UV-induced skin carcinogenesis. Together these studies demonstrate that COX-2 expression/activity is critical to the development of UV-related nonmelanoma skin cancers.
Rundhaug
Joyce E
JE
Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Science Park--Research Division, Smithville, Texas 78957, USA.
Mikulec
Carol
C
Pavone
Amy
A
Fischer
Susan M
SM
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000528:radiation effects*; D051546:Cyclooxygenase 2 / Q000502:physiology*; D006801:Humans; D009381:Neoplasms, Radiation-Induced / Q000209:etiology*; D012878:Skin Neoplasms / Q000201:enzymology / Q000209:etiology*; D014466:Ultraviolet Rays
D051546:Cyclooxygenase 2