[6]-Gingerol inhibits COX-2 expression by blocking the activation of p38 MAP kinase and NF-κB in phorbol ester-stimulated mouse skin

被引:217
作者
Kim, SO
Kundu, JK
Shin, YK
Park, JH
Cho, MH
Kim, TY
Surh, YJ [1 ]
机构
[1] Seoul Natl Univ, Coll Pharm, Seoul 151742, South Korea
[2] Seoul Natl Univ, Coll Vet Med, Seoul 151742, South Korea
[3] Seoul Natl Univ, Sch Agr Biotechnol, Seoul 151742, South Korea
[4] Catholic Univ Korea, Coll Med, Seoul 150010, South Korea
关键词
chemoprevention; cyclooxygenase-2; 6]-gingerol; p38; MAPK; NF-kappa B; mouse skin;
D O I
10.1038/sj.onc.1208446
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
[6]-Gingerol, a pungent ingredient of ginger (Zingiber officinale Roscoe, Zingiberaceae), has a wide array of pharmacologic effects. The present study was aimed at unraveling the molecular mechanisms underlying previously reported antitumor promoting effects of [6]- gingerol in mouse skin in vivo. One of the well-recognized molecular targets for chemoprevention is cyclooxygenase-2 (COX-2) that is abnormally upregulated in many premalignant and malignant tissues and cells. In our present study, topical application of [6]- gingerol inhibited COX-2 expression in mouse skin stimulated with a prototype tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Since the transcription factor nuclear factor-kappaB (NF-KB) is known to regulate COX-2 induction, we attempted to determine the effect of [6]- gingerol on TPA-induced activation of NF-KB. Pretreatment with [6]-gingerol resulted in a decrease in both TPA-induced DNA binding and transcriptional activities of NF-KB through suppression of IKB alpha degradation and p65 nuclear translocation. Phosphorylation of both IKB alpha and p65 was substantially blocked by [6]-gingerol. In addition, [6]-gingerol inhibited TPA-stimulated interaction of phospho-p65-(Ser-536) with cAMP response element binding protein-binding protein, a transcriptional coactivator of NF-KB. Moreover, [6]-gingerol prevented TPA-induced phosphorylation and catalytic activity of p38 mitogen-activated protein ( MAP) kinase that regulates COX-2 expression in mouse skin. The p38 MAP kinase inhibitor SB203580 attenuated NF-KB activation and subsequent COX-2 induction in TPA-treated mouse skin. Taken together, our data suggest that [6]-gingerol inhibits TPA-induced COX-2 expression in mouse skin in vivo by blocking the p38 MAP kinase-NF-KB signaling pathway.
引用
收藏
页码:2558 / 2567
页数:10
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