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

Laboratory of Molecular Carcinogenesis (LMC), National Institute of Environmental Health Sciences, Durham, North Carolina, United States
Cancer Research (Impact Factor: 9.33). 04/2007; 67(5):2015-21. DOI: 10.1158/0008-5472.CAN-06-3617
Source: PubMed


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/m(2)), and apoptotic signaling pathways were compared. Following exposure, apoptosis was 2.5-fold higher in COX-2-/- compared with WT mice. Because prostaglandin E(2) (PGE(2)) 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 (Ser(136) and Ser(155)), 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 PGE(2) production, and PGE(2), the EP2 agonist (butaprost) or EP4 agonist (PGE(1) alcohol), was applied. Indomethacin reduced PKA and Akt activation by approximately 60%, but PGE(2) and the agonists restored their activities. Furthermore, both agonists decreased apoptosis in COX-2-/- mice by 50%. The data suggest that COX-2-generated PGE(2) has antiapoptotic roles in UVB-exposed mouse skin that involves EP2- and EP4-mediated signaling.

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Available from: Kyung-Soo Chun, Jul 11, 2014
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    • "These data also indicated that the basal levels of cyclin D1 and cyclin D2 in non-UVB-exposed HF-diet-fed mice were higher than non-UVB-exposed C-diet-fed mice. The risk of UVB-induced skin tumors is associated with various signaling pathways, including the activation of the cell survival kinases, such as phosphatidylinositol-3 kinase (PI3K)/Akt (Chun et al., 2007; Luo et al., 2003; Nomura et al., 2001; Tyrrell, 1996). To examine whether the effects of UVB irradiation on PI3K survival signals are affected by the administration of the HF-diet, we determined the levels of PI3K/Akt in skin samples. "
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    ABSTRACT: Previously, we showed that administration of a high-fat diet (HF-diet) to C57BL/6 mice exacerbates their response to short-term UVB radiation-induced inflammation in the skin. To explore the effects of a HF-diet on UVB-induced tumorigenesis, we have used the SKH-1 hairless mouse model in which the mice are exposed to UVB radiation (180mJ/cm(2)) three times a week for 24weeks. The development of UVB-induced skin tumors was rapid and the tumor multiplicity and tumor size were significantly higher (P<0.01-0.005) in the mice fed a HF-diet than the mice fed a control-diet (C-diet). Moreover, the malignant progression of UVB-induced papillomas to carcinomas was higher in HF-diet-fed mice. On analysis of tumors and tumor-uninvolved skin samples from the tumor-bearing mice, we found that administration of a HF-diet significantly enhanced the levels of UVB-induced expression of cyclooxygenase-2 (COX-2), prostaglandin E2 (P<0.01), and PGE2 receptors, and activation of NF-κB in the UVB-exposed skin as well as in tumors. In addition the HF-diet enhanced the expression of proinflammatory cytokines, including tumor necrosis factor-α (P<0.01), interleukin (IL)-1β (P<0.01) and IL-6 (P<0.05) in the UVB-exposed skin as well as in tumors. Western blot analysis revealed that HF-diet enhanced the levels of epidermal cell proliferation, phosphatidylinositol 3-kinase and phosphorylation of Akt at Ser(473) in UVB-exposed skin and skin tumors. Collectively, these data demonstrate that the regular consumption of a HF-diet increases the risk of photocarcinogenesis in mice and that this is associated with enhanced expression of inflammatory mediators in the UVB-exposed skin and tumors.
    Full-text · Article · Nov 2013 · Toxicology and Applied Pharmacology
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    • "to the shaved dorsal skin 30 minutes before UVB exposure. PGE 2 (50 μg in 0.2 ml of acetone) was applied to the COX-2–deficient mouse skin after UVB exposure [16] [17]. Control animals were treated topically with acetone (0.2 ml of acetone). "
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    ABSTRACT: Exposure of mice to UV radiation results in suppression of the contact hypersensitivity (CHS) response. Here, we report that the UV-induced suppression of CHS is associated with increases in the levels of cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and PGE2 receptors in the exposed skin. UV radiation-induced suppression of CHS was inhibited by topical treatment of the skin with celecoxib or indomethacin (inhibitors of COX-2) or AH6809 (an EP2 antagonist). Moreover, mice deficient in COX-2 were found to be resistant to UV-induced suppression of CHS. The exposure of wild-typemice to UVB radiation resulted in DNA hypermethylation, increased DNA methyltransferase (Dnmt) activity, and elevated levels of Dnmt1, Dnmt3a, and Dnmt3b proteins in the skin, and these responses were downregulated on topical treatment of the site of exposure after irradiation with indomethacin or EP2 antagonist. Topical treatment of UVB-exposed COX-2-deficient mice with PGE2 enhanced the UVB-induced suppression of CHS as well as global DNA methylation and elevated the levels of Dnmt activity and Dnmt proteins in the skin. Intraperitoneal injection of 5-aza-2'-deoxycytidine (5-Aza-dc), a DNA demethylating agent, restored the CHS response to 2,4-dinitrofluorobenzene in UVB-exposed skin and this was associated with the reduction in global DNA methylation and Dnmt activity and reduced levels of Dnmt proteins. Furthermore, treatment with 5-Aza-dc reversed the effect of PGE2 on UV-induced suppression of CHS in COX-2-deficient mice. These findings reveal a previously unrecognized role for PGE2 in the promotion of UVB-induced immunosuppression and indicate that it is mediated through PGE2 regulation of DNA methylation.
    Full-text · Article · Jul 2013 · Neoplasia (New York, N.Y.)
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    • "They compared the protein levels of all the EP receptors following UV exposure of COX-2 null and wild-type mice and found that although EP1, EP2, and EP4 were induced in wild-type mice, EP2 and EP4 levels were 50% lower in the COX-2 null mice. The levels of activated PKA and AKT were also reduced in the COX-2 nulls, as were the phosphorylated forms of the anti-apoptotic protein Bad, pBadser136 and pBadser155, which are downstream products of activated AKT and PKA, respectively [55]. These findings suggested that both EP2 and EP4 are responsible for the anti-apoptotic effects of PGE2 in the setting of UV-induced COX-2. "
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    ABSTRACT: One of the most common features of exposure of skin to ultraviolet (UV) light is the induction of inflammation, a contributor to tumorigenesis, which is characterized by the synthesis of cytokines, growth factors and arachidonic acid metabolites, including the prostaglandins (PGs). Studies on the role of the PGs in non-melanoma skin cancer (NMSC) have shown that the cyclooxygenase-2 (COX-2) isoform of the cyclooxygenases is responsible for the majority of the pathological effects of PGE(2). In mouse skin models, COX-2 deficiency significantly protects against chemical carcinogen- or UV-induced NMSC while overexpression confers endogenous tumor promoting activity. Current studies are focused on identifying which of the G protein-coupled EP receptors mediate the tumor promotion/progression activities of PGE(2) and the signaling pathways involved. As reviewed here, the EP1, EP2, and EP4 receptors, but not the EP3 receptor, contribute to NMSC development, albeit through different signaling pathways and with somewhat different outcomes. The signaling pathways activated by the specific EP receptors are context specific and likely depend on the level of PGE(2) synthesis, the differential levels of expression of the different EP receptors, as well as the levels of expression of other interacting receptors. Understanding the role and mechanisms of action of the EP receptors potentially offers new targets for the prevention or therapy of NMSCs.
    Full-text · Article · Dec 2011 · CANCER AND METASTASIS REVIEW
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