Cyclooxygenase‐2 deficiency increases epidermal apoptosis and impairs recovery following acute UVB exposure

Akunda, Jacqueline K.; Chun, Kyung‐Soo; Sessoms, Alisha R.; Lao, Huei-Chen; Fischer, Susan M.; Langenbach, Robert

doi:10.1002/mc.20290

Cited by 31 publications

(50 citation statements)

References 29 publications

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“…We recently reported that the deficiency of COX-2 reduced UVB-induced PGE 2 levels by 35% and increased epidermal apoptosis compared with WT and COX-1À/À mice (24). Figure 1A shows an independent study comparing the levels of apoptosis in WT and COX-2À/À mice at 24 h after UVB exposure.…”

Section: Resultsmentioning

confidence: 96%

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

Chun

Akunda²,

Langenbach³

2007

Cancer Research

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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-2À/À 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-2À/À 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-2À/À 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-2À/À 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-2À/À mice. Furthermore, p-Bad (Ser 136 and Ser 155 ), antiapoptotic products of activated Akt and PKA, respectively, were significantly reduced in UVB-exposed COX-2À/À 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 f60%, but PGE 2 and the agonists restored their activities. Furthermore, both agonists decreased apoptosis in COX-2À/À mice by 50%. The data suggest that COX-2-generated PGE 2 has antiapoptotic roles in UVBexposed mouse skin that involves EP2-and EP4-mediated signaling. [Cancer Res 2007;67(5):2015-21]

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Section: Resultsmentioning

confidence: 96%

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

Chun

Akunda²,

Langenbach³

2007

Cancer Research

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“…These reports have shown that apigenin treatment downmodulates both basal and UVB-induced cyclooxygenase (COX)-2 expression in keratinocytes. A number of other laboratories have shown that selective COX-2 inhibition can reduce tumor formation (30)(31)(32)(33)(34), presumably by increasing apoptosis (35,36) in cells that have carcinogenic potential. A recent study by Akunda and colleagues (34) reported COX-2 deficiency significantly increased UVB-induced epidermal apoptosis, in agreement with previous findings by Tripp et al (32).…”

Section: Discussionmentioning

confidence: 99%

Enhancement of UVB-Induced Apoptosis by Apigenin in Human Keratinocytes and Organotypic Keratinocyte Cultures

et al. 2008

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Topical application of the bioflavonoid 4 ¶,5,7-trihydroxyflavone (apigenin) to mouse skin effectively reduces the incidence and size of skin tumors caused by UVB exposure. The ability to act as a chemopreventive compound indicates that apigenin treatment alters the molecular events initiated by UVB exposure; however, the effects of apigenin treatment on UVB-irradiated keratinocytes are not fully understood. In the present study, we have used three models of human keratinocytes to study the effect of apigenin treatment on UVB-induced apoptosis: HaCaT human keratinocyte cells, primary keratinocyte cultures isolated from human neonatal foreskin, and human organotypic keratinocyte cultures. Each keratinocyte model was exposed to a moderate dose of UVB (300-1,000 J/m 2 ), then treated with apigenin (0-50 Mmol/L), and harvested to assess apoptosis by Western blot analysis for poly(ADP)ribose polymerase cleavage, annexin-V staining by flow cytometry, and/or the presence of sunburn cells. Apigenin treatment enhanced UVB-induced apoptosis >2-fold in each of the models tested. When keratinocytes were exposed to UVB, apigenin treatment stimulated changes in Bax localization and increased the release of cytochrome c from the mitochondria compared with UVB exposure alone. Overexpression of the antiapoptotic protein Bcl-2 and expression of a dominant-negative form of Fas-associated death domain led to a reduction in the ability of apigenin to enhance UVB-induced apoptosis. These results suggest that enhancement of UVB-induced apoptosis by apigenin treatment involves both the intrinsic and extrinsic apoptotic pathways. The ability of apigenin to enhance UVBinduced apoptosis may explain, in part, the photochemopreventive effects of apigenin. [Cancer Res 2008;68(8):3057-65]

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“…In contrast, targeted Cox-2 gene deletion in myeloid cells does not modulate UVB skin tumor induction. (20). Pharmacologic studies also suggest that COX-2 plays a role in UVB-induced skin hyperplasia in SKH-1 hairless mice (21).…”

Section: Targeted Cox-2 Deletion In Skin Epidermal Cells Reduces Uvb mentioning

confidence: 99%

Cell-type-specific roles for COX-2 in UVB-induced skin cancer

et al. 2014

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In human tumors, and in mouse models, cyclooxygenase-2 (COX-2) levels are frequently correlated with tumor development/ burden. In addition to intrinsic tumor cell expression, COX-2 is often present in fibroblasts, myofibroblasts and endothelial cells of the tumor microenvironment, and in infiltrating immune cells. Intrinsic cancer cell COX-2 expression is postulated as only one of many sources for prostanoids required for tumor promotion/progression. Although both COX-2 inhibition and global Cox-2 gene deletion ameliorate ultraviolet B (UVB)-induced SKH-1 mouse skin tumorigenesis, neither manipulation can elucidate the cell type(s) in which COX-2 expression is required for tumorigenesis; both eliminate COX-2 activity in all cells. To address this question, we created Cox-2 flox/flox mice, in which the Cox-2 gene can be eliminated in a cell-type-specific fashion by targeted Cre recombinase expression. Cox-2 deletion in skin epithelial cells of SKH-1 Cox-2 flox/flox ;K14Cre + mice resulted, following UVB irradiation, in reduced skin hyperplasia and increased apoptosis. Targeted epithelial cell Cox-2 deletion also resulted in reduced tumor incidence, frequency, size and proliferation rate, altered tumor cell differentiation and reduced tumor vascularization. Moreover, Cox-2 flox/flox ;K14Cre + papillomas did not progress to squamous cell carcinomas. In contrast, Cox-2 deletion in SKH-1 Cox-2 flox/flox ; LysMCre + myeloid cells had no effect on UVB tumor induction. We conclude that (i) intrinsic epithelial COX-2 activity plays a major role in UVB-induced skin cancer, (ii) macrophage/myeloid COX-2 plays no role in UVB-induced skin cancer and (iii) either there may be another COX-2-dependent prostanoid source(s) that drives UVB skin tumor induction or there may exist a COX-2-independent pathway(s) to UVB-induced skin cancer.

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Cyclooxygenase‐2 deficiency increases epidermal apoptosis and impairs recovery following acute UVB exposure

Cited by 31 publications

References 29 publications

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

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

Enhancement of UVB-Induced Apoptosis by Apigenin in Human Keratinocytes and Organotypic Keratinocyte Cultures

Cell-type-specific roles for COX-2 in UVB-induced skin cancer

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