Cyanidin suppresses ultraviolet B-induced COX-2 expression in epidermal cells by targeting MKK4, MEK1, and Raf-1.
Skin cancer is the most frequently diagnosed cancer in the United States. Ultraviolet B (UVB) rays (wavelength: 280-320nm) play a pivotal role in the development of skin cancer by inducing the expression of inflammatory proteins such as cyclooxygenase-2 (COX-2). Cyanidin, the most plentiful of the plant pigments known as anthocyanidins, is a potent chemopreventive agent. In the present study, we examined the molecular mechanisms underlying the chemopreventive activity of cyanidin and identified its molecular targets. Cyanidin inhibited UVB-induced COX-2 expression and prostaglandin E(2) secretion in the epidermal skin cell line JB6 P+ by suppressing the transactivation of nuclear factor-kappaB and activator protein-1 which are well-known transcription factors regulated by mitogen-activated protein kinase. Cyanidin markedly inhibited the phosphorylation of JNK1/2, ERK1/2, and MEK1/2 than the of MKK4 and Raf-1, two upstream kinases of JNK1/2, ERK1/2, and MEK1/2. Cyanidin significantly suppressed the activities of MKK4, MEK1, and Raf-1 through direct binding. Transient transfection of a small interfering RNA specific for MKK4 inhibited the UVB-induced expression of COX-2 in JB6 P+ cells, as did the expression of a dominant-negative ERK2 mutant. We conclude that MKK4, MEK1, and Raf-1 are targets of cyanidin for the suppression of UVB-induced COX-2 expression.
Kim
Jong-Eun
JE
WCU, Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Republic of Korea.
Kwon
Jung Yeon
JY
Seo
Sang Kwon
SK
Son
Joe Eun
JE
Jung
Sung Keun
SK
Min
So Yun
SY
Hwang
Mun Kyung
MK
Heo
Yong-Seok
YS
Lee
Ki Won
KW
Lee
Hyong Joo
HJ
D000818:Animals; D000872:Anthocyanins / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000187:drug effects*; D015232:Dinoprostone / Q000096:biosynthesis; D004817:Epidermis / Q000187:drug effects* / Q000201:enzymology / Q000528:radiation effects; D047468:Immunoprecipitation; D048369:MAP Kinase Kinase 1 / Q000187:drug effects* / Q000502:physiology; D048670:MAP Kinase Kinase 4 / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D019908:Proto-Oncogene Proteins c-raf / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects; D014466:Ultraviolet Rays / Q000009:adverse effects*
D000872:Anthocyanins; D018808:Transcription Factor AP-1; C017154:cyanidin; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019908:Proto-Oncogene Proteins c-raf; D048369:MAP Kinase Kinase 1; D048670:MAP Kinase Kinase 4; C482127:Map2k1 protein, mouse; D015232:Dinoprostone