Curcumin inhibits phorbol ester-induced expression of cyclooxygenase-2 in mouse skin through suppression of extracellular signal-regulated kinase activity and NF-κB activation
Curcumin inhibits phorbol ester-induced expression of cyclooxygenase-2 in mouse skin through suppression of extracellular signal-regulated kinase activity and NF-κB activation
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DOI：
10.1093/carcin/bgg107
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发表时间：
2003-09-01
期刊：
影响因子：
4.7
通讯作者：
Surh, YJ
中科院分区：
文献类型：
--
作者：
Chun, KS;Keum, YS;Surh, YJ
近年来，人们一直在努力寻找天然存在的物质来干预癌变。从膳食或药用植物中提取的许多成分已被发现具有实质性的化学预防特性。姜黄素（Curcuma longa L.，姜黄科）是姜黄的一种黄色着色成分，已被证明具有抑制实验性癌变和诱变的作用，但其化学预防作用的分子机制尚不清楚。在本研究中，我们评估了姜黄素对12-O-十四烷醇-13-乙酸（TPA）诱导的雌性ICR小鼠皮肤环氧化酶-2 （COX-2）表达的影响。外用10 nmol TPA局部刺激雌性ICR小鼠背侧皮肤，cox-2 mRNA和蛋白表达分别在大约1和4 h时达到最大。当在TPA前30分钟局部应用于小鼠剃须背部时，姜黄素以剂量相关的方式抑制COX-2蛋白的表达。tpa处理小鼠皮肤的免疫组化分析显示，COX-2的表达增强，主要位于表皮层，姜黄素预处理明显抑制COX-2的表达。姜黄素处理减弱了TPA刺激的小鼠皮肤NF-kappaB激活，这与其阻断抑制蛋白IkappaBalpha的降解以及随后p65亚基向细胞核的易位有关。TPA通过磷酸化细胞外信号调节激酶（ERK）1/2和p38丝裂原活化蛋白（MAP）激酶（NF-kappaB的上游）导致快速激活。MEK1/2抑制剂U0126强烈抑制NF-kappaB激活，而p38抑制剂SB203580未能阻断tpa诱导的小鼠皮肤NF-kappaB激活。此外，U0126阻断了TPA对IkappaBalpha的磷酸化，从而阻断了NF-kappaB的核易位。姜黄素抑制小鼠皮肤ERK1/2的催化活性。综上所述，通过抑制ERK活性和NF-kappaB激活来抑制COX-2表达可能代表了先前报道的这种植物化学物质在小鼠皮肤肿瘤发生中的抗肿瘤促进作用的分子机制。
Recently, there have been considerable efforts to search for naturally occurring substances for the intervention of carcinogenesis. Many components derived from dietary or medicinal plants have been found to possess substantial chemopreventive properties. Curcumin, a yellow coloring ingredient of turmeric (Curcuma longa L., Zingiberaceae), has been shown to inhibit experimental carcinogenesis and mutagenesis, but molecular mechanisms underlying its chemopreventive activities remain unclear. In the present work, we assessed the effects of curcumin on 12-O- tetradecanoylphorbol-13-acetate (TPA)-induced expression of cyclooxygenase-2 (COX-2) in female ICR mouse skin. Topical application of the dorsal skin of female ICR mice with 10 nmol TPA led to maximal induction of cox-2 mRNA and protein expression at similar to1 and 4 h, respectively. When applied topically onto shaven backs of mice 30 min prior to TPA, curcumin inhibited the expression of COX-2 protein in a dose-related manner. Immunohistochemical analysis of TPA-treated mouse skin revealed enhanced expression of COX-2 localized primarily in epidermal layer, which was markedly suppressed by curcumin pre-treatment. Curcumin treatment attenuated TPA- stimulated NF-kappaB activation in mouse skin, which was associated with its blockade of degradation of the inhibitory protein IkappaBalpha and also of subsequent translocation of the p65 subunit to nucleus. TPA treatment resulted in rapid activation via phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein (MAP) kinases, which are upstream of NF-kappaB. The MEK1/2 inhibitor U0126 strongly inhibited NF-kappaB activation, while p38 inhibitor SB203580 failed to block TPA-induced NF-kappaB activation in mouse skin. Furthermore, U0126 blocked the IkappaBalpha phosphorylation by TPA, thereby blocking the nuclear translocation of NF-kappaB. Curcumin inhibited the catalytic activity of ERK1/2 in mouse skin. Taken together, suppression of COX-2 expression by inhibiting ERK activity and NF-kappaB activation may represent molecular mechanisms underlying previously reported antitumor promoting effects of this phytochemical in mouse skin tumorigenesis.