TitleDelphinidin suppresses ultraviolet B-induced cyclooxygenases-2 expression through inhibition of MAPKK4 and PI-3 kinase.
Publication TypeJournal Article
Year of Publication2009
AuthorsKwon, JYeon, Lee, KWon, Kim, J-E, Jung, SKeun, Kang, NJoo, Hwang, MKyung, Heo, Y-S, Bode, AM, Dong, Z, Lee, HJoo
JournalCarcinogenesis
Volume30
Issue11
Pagination1932-40
Date Published2009 Nov
ISSN1460-2180
KeywordsAnimals, Anthocyanins, Cells, Cultured, Cyclooxygenase 2, Dietary Carbohydrates, Dinoprostone, Enzyme Activation, Epidermis, Female, MAP Kinase Kinase 4, Mice, Mice, Inbred ICR, NF-kappa B, Phosphatidylinositol 3-Kinases, Skin Neoplasms, Transcription Factor AP-1, Ultraviolet Rays, Up-Regulation
Abstract

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-kappaB, 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.

DOI10.1093/carcin/bgp216
Alternate JournalCarcinogenesis
PubMed ID19776176
PubMed Central IDPMC2783004
Grant ListCA120388 / CA / NCI NIH HHS / United States
CA111536 / CA / NCI NIH HHS / United States
CA 81064 / CA / NCI NIH HHS / United States
CA27502 / CA / NCI NIH HHS / United States
CA88961 / CA / NCI NIH HHS / United States