Roles Of Cyclooxygenase-1 and -2 In UV-induced Skin Cancer

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Epidemiology studies indicate that ultraviolet (UV) radiation causes skin damage and is a major environmental agent in the causation of skin cancer. While it has been established that both the constitutive and inducible forms of cyclooxygenase (COX-1 and COX-2, respectively) play important roles in chemical induced skin tumors, the contribution of these two enzymes to UV light-induced skin skin damage and tumor development is poorly understood. The cyclooxygenases, COX-1 and COX-2, are involved in cutaneous responses to both acute and chronic UV exposure. In previous studies, wild-type (WT), COX-1-/- and COX-2-/- mice were used to determine the influence of the individual isoform on mouse skin responses to acute UVB treatment. Immunohistochemistry and Western analysis indicated that COX-2, and not COX-1, was induced by UVB, but COX-1 remained the major source of prostaglandin (PG) production. UVB exposure significantly increased epidermal damage in all genotypes compared to untreated mice, however, the extent of epidermal damage and number of apoptotic cells was significantly greater in COX-2-/- mice. To better understand the contribution of COX-1 and COX-2 to UV effects on skin, we investigated the effects of COX deficiency on the expression of epidermal cell survival effectors following acute UVB exposure. It was observed that induction of the transcription factor p-STAT was significantly reduced in the epidermis of COX-2-/- mice compared to WT mice following UVB exposure. Furthermore survivin levels were also significantly reduced in the COX-2-/- epidermis compared to WT mice. To show that these effects were dependent on reduced PG production in COX-2-/- mice, Indomethacin treatment of WT mice also reduced p-STAT and survivin levels following UVB exposure. In addition to reduced p-STAT and survivin in UV exposed COX-2-/- mice, the levels of p-ERK1/2, EGFR and Ras were also observed to be reduced in the epidermis of UV exposed COX-2-/- mice. Overall, the data indicate that COX-2 protects against the acute UVB-induced skin damage affects, but that continuous induction of COX-2 and PG levels may contribute to skin cancer in chronic UVB exposure.