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

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Abstract

[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-κB) is known to regulate COX-2 induction, we attempted to determine the effect of [6]-gingerol on TPA-induced activation of NF-κB. Pretreatment with [6]-gingerol resulted in a decrease in both TPA-induced DNA binding and transcriptional activities of NF-κB through suppression of IκBα degradation and p65 nuclear translocation. Phosphorylation of both IκBα 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-κB. 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-κB 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-κB signaling pathway.

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Acknowledgements

This work was supported by the National Research Laboratory Fund (allocated to Y-J Surh) from the Ministry of Science and Technology, Republic of Korea. We acknowledge the technical support by Professor Yong-Sang Song of Seoul National University Hospital for immunohistochemical analyses.

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Author notes

  1. Sue Ok Kim and Joydeb Kumar Kundu: These two authors contributed equally to this work

Authors and Affiliations

  1. College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea

    Sue Ok Kim, Joydeb Kumar Kundu, Young Kee Shin & Young-Joon Surh

  2. College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul National University, Seoul, 151-742, South Korea

    Jin-Hong Park & Myung-Haing Cho

  3. College of Medicine, The Catholic University of Korea, Seoul, 150-010, South Korea

    Tae-Yoon Kim

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  1. Sue Ok Kim
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  2. Joydeb Kumar Kundu
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  6. Tae-Yoon Kim
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Correspondence to Young-Joon Surh.

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Kim, S., Kundu, J., Shin, Y. et al. [6]-Gingerol inhibits COX-2 expression by blocking the activation of p38 MAP kinase and NF-κB in phorbol ester-stimulated mouse skin. Oncogene 24, 2558–2567 (2005). https://doi.org/10.1038/sj.onc.1208446

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