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Cyclooxygenase-2 Inhibits UVB-Induced Apoptosis in Mouse Skin by Activating the Prostaglandin E₂ Receptors, EP2 and EP4

Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina

Requests for reprints: Robert Langenbach, National Institute of Environmental Health Sciences, M. D. C4-09, P.O. Box 12233, Research Triangle Park, NC 27709. Phone: 919-541-7558; Fax: 919-541-1460; E-mail: langenb1{at}niehs.nih.gov.

Cyclooxygenase-2 (COX-2) is induced by UVB light and reduces UVB-induced epidermal apoptosis; however, the mechanism is unclear. Therefore, wild-type (WT) and COX-2–/– mice were acutely treated with UVB (5 kJ/m²), and apoptotic signaling pathways were compared. Following exposure, apoptosis was 2.5-fold higher in COX-2–/– compared with WT mice. Because prostaglandin E₂ (PGE₂) is the major UV-induced prostaglandin and manifests its activity via four receptors, EP1 to EP4, possible differences in EP signaling were investigated in WT and COX-2–/– mice. Following UVB exposure, protein levels of EP1, EP2, and EP4 were elevated in WT mice, but EP2 and EP4 levels were 50% lower in COX-2–/– mice. Activated cyclic AMP-dependent protein kinase (PKA) and Akt are downstream in EP2 and EP4 signaling, and their levels were reduced in UVB-exposed COX-2–/– mice. Furthermore, p-Bad (Ser¹³⁶ and Ser¹⁵⁵), antiapoptotic products of activated Akt and PKA, respectively, were significantly reduced in UVB-exposed COX-2–/– mice. To further study the roles of EP2 and EP4, UVB-exposed CD-1 mice were topically treated with indomethacin to block endogenous PGE₂ production, and PGE₂, the EP2 agonist (butaprost) or EP4 agonist (PGE₁ alcohol), was applied. Indomethacin reduced PKA and Akt activation by 60%, but PGE₂ and the agonists restored their activities. Furthermore, both agonists decreased apoptosis in COX-2–/– mice by 50%. The data suggest that COX-2–generated PGE₂ has antiapoptotic roles in UVB-exposed mouse skin that involves EP2- and EP4-mediated signaling. [Cancer Res 2007;67(5):2015–21]

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