Resveratrol modulates phorbol ester-induced pro-inflammatory signal transduction pathways in mouse skin in vivo:: NF-κB and AP-1 as prime targets
Resveratrol modulates phorbol ester-induced pro-inflammatory signal transduction pathways in mouse skin in vivo:: NF-κB and AP-1 as prime targets
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DOI：
10.1016/j.bcp.2006.08.005
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发表时间：
2006-11-30
影响因子：
5.8
通讯作者：
Surh, Young-Joon
中科院分区：
文献类型：
--
作者：
Kundu, Joydeb Kumar;Shin, Young Kee;Surh, Young-Joon
细胞内信号网络的功能异常导致关键细胞成分维持的稳态被破坏，从而加速癌前和恶性转化。多种证据表明，环氧化酶-2 （COX-2）的表达升高与肿瘤发生有因果关系。暴露于氧化/促炎刺激会开启由多种激酶和转录因子介导的信号阵列，这可能导致COX-2的异常表达。我们试图揭示肿瘤启动子12- o - tetradecanoylphorol -13-acetate （TPA）刺激小鼠皮肤中COX-2表达升高的信号转导途径，以及白藜芦醇（一种已知具有潜在化学预防作用的植物抗毒素）对其的调节。我们的研究表明，局部应用TPA通过激活核因子- κ B （nf - κ B）来诱导小鼠皮肤中COX-2的表达，而核因子- κ B受上游I κ B激酶（IKK）或有丝分裂原活化蛋白（MAP）激酶的差异调节。除了NF-kappa B， p38 MAP激酶介导的激活因子蛋白1 （AP-1）的激活也归因于tpa诱导小鼠皮肤中COX-2的表达。在MAP激酶中，细胞外信号调节蛋白激酶（ERK）和p38 MAP激酶已被证明可调节tpa诱导的NF-kappa B激活，而p38 MAP激酶和c- jun - n末端激酶在体内优先参与tpa诱导的小鼠皮肤AP-1的激活。本文主要研究白藜芦醇对tpa刺激小鼠皮肤中COX-2异常表达的细胞内信号通路的调节，以揭示白藜芦醇促进抗肿瘤作用的分子机制。(c) 2006年Elsevier Inc.出版
Functional abnormalities of intracellular signaling network cause the disruption in homeostasis maintained by critical cellular components, thereby accelerating premalignant and malignant transformation. Multiple lines of evidence suggest that an elevated expression of cyclooxygenase-2 (COX-2) is causally linked to tumorigenesis. The exposure to oxidative/pro-inflammatory stimuli turns on signaling arrays mediated by diverse classes of kinases and transcription factors, which may lead to aberrant expression of COX-2. We have attempted to unravel the signal transduction pathways involved in elevated COX-2 expression in mouse skin stimulated with a prototype tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and its modulation by resveratrol, a phytoalexin known to exert potential chemopreventive effects. Our study revealed that topical application of TPA induced COX-2 expression in mouse skin via activation of nuclear factor-kappa B (NF-kappa B), which is regulated by upstream I kappa B kinase (IKK) or differentially by mitogen-activated protein (MAP) kinases. Besides NF-kappa B, the p38 MAP kinase-mediated activation of activator protein-1 (AP-1) has also been attributed to TPA-induced COX-2 expression in mouse skin. Among the MAP kinases, extracellular signal-regulated protein kinase (ERK) and p38 MAP kinase have been shown to regulate TPA-induced NF-kappa B activation, while p38 MAP kinase and c-Jun-N-terminal kinase are preferentially involved in TPA-induced activation of AP-1 in mouse skin in vivo. This commentary focuses on resveratrol modulation of intracellular signaling pathways involved in aberrant COX-2 expression in TPA-stimulated mouse skin to delineate molecular mechanisms underlying antitumor promoting effects of resveratrol. (c) 2006 Published by Elsevier Inc.