Delphinidin suppresses ultraviolet B-induced cyclooxygenases-2 expression through inhibition of MAPKK4 and PI-3 kinase.
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.
Kwon
Jung Yeon
JY
Major in Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul 151-742, Republic of Korea.
Lee
Ki Won
KW
Kim
Jong-Eun
JE
Jung
Sung Keun
SK
Kang
Nam Joo
NJ
Hwang
Mun Kyung
MK
Heo
Yong-Seok
YS
Bode
Ann M
AM
Dong
Zigang
Z
Lee
Hyong Joo
HJ
D000818:Animals; D000872:Anthocyanins / Q000494:pharmacology*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D004040:Dietary Carbohydrates / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D004817:Epidermis / Q000201:enzymology* / Q000528:radiation effects*; D005260:Female; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors*; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012878:Skin Neoplasms / Q000201:enzymology / Q000517:prevention & control; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014466:Ultraviolet Rays; D015854:Up-Regulation / Q000187:drug effects / Q000528:radiation effects
D000872:Anthocyanins; D004040:Dietary Carbohydrates; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018808:Transcription Factor AP-1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D048670:MAP Kinase Kinase 4; C017185:delphinidin; D015232:Dinoprostone