-Gingerol inhibits COX-2 expression by blocking the activation of p38 MAP kinase and NF-kBB in phorbol ester-stimulated mouse skin
- Kim, Sue Ok; Kundu, Joydeb Kumar; Shin, Young Kee; Park, Jin-Hong; Cho, Myung-Haing; Kim, Tae-Yoon; Surh, Young-Joon
- Issue Date
- Nature Publishing Group
- Oncogene, 24, 2558–2567
- -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 -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 -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-B) is known to regulate COX-2 induction, we attempted to determine the effect of -gingerol on TPA-induced activation of NF-B. Pretreatment with -gingerol resulted in a decrease in both TPA-induced DNA binding and transcriptional activities of NF-B through suppression of IB degradation and p65 nuclear translocation. Phosphorylation of both IB and p65 was substantially blocked by -gingerol. In addition, -gingerol inhibited TPA-stimulated interaction of phospho-p65-(Ser-536) with cAMP response element binding protein-binding protein, a transcriptional coactivator of NF-B. Moreover, -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-B activation and subsequent COX-2 induction in TPA-treated mouse skin. Taken together, our data suggest that -gingerol inhibits TPA-induced COX-2 expression in mouse skin in vivo by blocking the p38 MAP kinase-NF-B signaling pathway.
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