Inhibition of AP-1 and MAPK signaling and activation of Nrf2/ARE pathway by quercitrin
Inhibition of AP-1 and MAPK signaling and activation of Nrf2/ARE pathway by quercitrin
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DOI：
10.3892/ijo_00000475
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发表时间：
2010-01-01
影响因子：
5.2
通讯作者：
Shi, Xianglin
中科院分区：
文献类型：
--
作者：
Ding, Min;Zhao, Jinshun;Shi, Xianglin
槲皮苷是黄酮类化合物的糖基化形式，广泛分布于自然界。大量的研究表明槲皮苷具有很强的抗氧化和抗癌活性。然而，分子机制知之甚少。本研究探讨了槲皮苷对小鼠JB 6细胞肿瘤促进作用的影响，JB 6细胞是筛选癌症化学预防剂和阐明分子机制的有效模型。槲皮苷阻断TPA诱导的JB 6 P（+）细胞的肿瘤转化。槲皮苷预处理JB 6细胞可下调UVB或TPA诱导的AP-1和NF-κ B的转录激活。在AP-1-荧光素酶转基因小鼠的皮肤中，用槲皮苷局部处理小鼠显著阻断TPA诱导的AP-1反式激活。进一步的研究表明，这些抑制作用似乎是通过抑制MAPK磷酸化介导的，包括ERK，p38激酶和JNKs。此外，槲皮苷刺激NF-E2相关因子（Nrf 2）和GST ARE-荧光素酶活性的激活。彗星实验表明槲皮苷能阻断UVB诱导的DNA损伤。据我们所知，这些结果提供了第一个证据表明，槲皮苷有助于抑制肿瘤转化阻断活化的MAPK途径和刺激细胞保护信号。此外，据我们所知，这些发现提供了第一个槲皮苷的抗癌作用的分子基础。
Quercitrin, glycosylated form of flavonoid compounds, is widely distributed in nature. Extensive studies have demonstrated that quercitrin exhibits strong antioxidant and anti-carcinogenic activities. However, the molecular mechanism is poorly understood. The present study examines the effects of quercitrin on tumor promotion in mouse JB6 cells, a validated model for screening cancer chemopreventive agents and elucidating the molecular mechanisms. Quercitrin blocked TPA-induced neoplastic transformation in JB6 P(+) cells. Pretreatment of JB6 cells with quercitrin down-regulated transactivation of AP-1 and NF-kappa B induced by UVB or TPA. In the skin of AP-1-luciferase transgenic mice, topical treatment of the mouse with quercitrin markedly blocked the TPA-induced AP-1 transactivation. Further studies indicated that these inhibitory actions appear to be mediated through the inhibition of MAPKs phosphorylation, including ERKs, p38 kinase, and JNKs. In addition, quercitrin stimulated the activation of NF-E2-related factor (Nrf2) and GST ARE-luciferase activity. Comet assays showed that quercitrin could block DNA damage induced by UVB. To our knowledge, these results provide the first evidence that quercitrin contributes to the inhibition of neoplastic transformation by blocking activation of the MAPK pathway and stimulation of cellular protection signaling. Moreover, to our knowledge, these findings provide the first molecular basis for the anti-carcinogenic action of quercitrin.