期刊
CARCINOGENESIS
卷 30, 期 11, 页码 1932-1940出版社
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgp216
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资金
- Hormel Foundation
- National Institutes of Health [CA27502, CA120388, CA111536, CA88961, CA 81064]
- World Class University [R31-2008-00-10056-0]
- Ministry of Education, Science and Technology [R012007-000-11957-0, M10510140004-08N1014-00410]
- BioGreen 21 Program [20070301-034-042]
- Rural Development Administration
- Technology Development Program for Agriculture and Forestry [107055-02]
- Ministry for Food, Agriculture, Forestry and Fisheries, Republic of Korea
Cyclooxygenase-2 (COX-2), a key mediator of inflammation, and its product, prostaglandin E-2 (PGE(2)), enhance carcinogenesis, particularly in skin. Ultraviolet (UV) B is the most carcinogenic component of solar irradiation, and a crucial role of COX-2 in UVB-mediated skin carcinogenesis has been reported. Here, we investigated the effects of delphinidin, an abundant dietary anthocyanin, on UVB-induced COX-2 upregulation and the underlying molecular mechanism. We found that delphinidin suppressed UVB-induced COX-2 expression in JB6 P+ mouse epidermal cells. COX-2 promoter activity and PGE(2) production were also suppressed by delphinidin treatment within non-cytotoxic concentrations. Activator protein-1 and nuclear factor-kappa B, crucial transcription factors involved in COX-2 expression, were activated by UVB and delphinidin abolished this activation. UVB-induced phosphorylation of c-Jun N-terminal kinase, p38 kinase and Akt was inhibited by delphinidin. The activities of mitogen-activated protein kinase kinase (MAPKK) 4 and phosphatidylinositol-3 kinase (PI-3K) were inhibited markedly by delphinidin. A pull-down assay using delphinidin-Sepharose beads revealed that delphinidin binds directly with MAPKK4 or PI-3K in a manner that was competitive with adenosine triphosphate. Moreover, in vivo investigations using mouse skin revealed that the upregulation of COX-2 expression, MAPKK4 activity and PI-3K activity induced by UVB was abolished with delphinidin treatment. Collectively, our results demonstrated that delphinidin targets MAPKK4 and PI-3K directly to suppress COX-2 overexpression, suggesting a potential protective role for delphinidin against UVB-mediated skin carcinogenesis.
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