Feng Rentian, Lu Yongju, Bowman Linda L, Qian Yong, Castranova Vincent, Ding Min
Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, USA.
J Biol Chem. 2005 Jul 29;280(30):27888-95. doi: 10.1074/jbc.M503347200. Epub 2005 Jun 8.
Chlorogenic acid, the ester of caffeic acid with quinic acid, is one of the most abundant polyphenols in the human diet. The antioxidant and anticarcinogenic properties of chlorogenic acid have been established in animal studies. However, little is known about the molecular mechanisms through which chlorogenic acid inhibits carcinogenesis. In this study, we found that chlorogenic acid inhibited the proliferation of A549 human cancer cells in vitro. The results of the soft agar assay indicated that chlorogenic acid suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic transformation of JB6 P+ cells in a dose-dependent manner. Pretreatment of JB6 cells with chlorogenic acid blocked UVB- or TPA-induced transactivation of AP-1 and NF-kappaB over the same dose range. At low concentrations, chlorogenic acid decreased the phosphorylation of c-Jun NH2-terminal kinases, p38 kinase, and MAPK kinase 4 induced by UVB/12-O-tetradecanoylphorbol-13-acetate, yet higher doses were required to inhibit extracellular signal-regulated kinases. Chlorogenic acid also increased the enzymatic activities of glutathione S-transferases (GST) and NAD(P)H: quinone oxidoreductase. Further studies indicated that chlorogenic acid could stimulate the nuclear translocation of Nrf2 (NF-E2-related factor) as well as subsequent induction of GSTA1 antioxidant response element (ARE)-mediated GST activity. The phosphatidylinositol 3-kinase pathway might be involved in the activation of Nrf2 translocation. These results provide the first evidence that chlorogenic acid could protect against environmental carcinogen-induced carcinogenesis and suggest that the chemopreventive effects of chlorogenic acid may be through its up-regulation of cellular antioxidant enzymes and suppression of ROS-mediated NF-kappaB, AP-1, and MAPK activation.
绿原酸是咖啡酸与奎尼酸的酯，是人类饮食中含量最为丰富的多酚类物质之一。动物研究已证实绿原酸具有抗氧化和抗癌特性。然而，关于绿原酸抑制致癌作用的分子机制却知之甚少。在本研究中，我们发现绿原酸在体外可抑制A549人癌细胞的增殖。软琼脂试验结果表明，绿原酸能以剂量依赖的方式抑制12 - O - 十四酰佛波醇 - 13 - 乙酸酯（TPA）诱导的JB6 P+细胞的肿瘤转化。在相同剂量范围内，用绿原酸预处理JB6细胞可阻断UVB或TPA诱导的AP - 1和NF - κB的反式激活。在低浓度下，绿原酸可降低UVB/12 - O - 十四酰佛波醇 - 13 - 乙酸酯诱导的c - Jun氨基末端激酶、p38激酶和丝裂原活化蛋白激酶激酶4的磷酸化，但需要更高剂量才能抑制细胞外信号调节激酶。绿原酸还可提高谷胱甘肽S - 转移酶（GST）和NAD(P)H：醌氧化还原酶的酶活性。进一步研究表明，绿原酸可刺激Nrf2（NF - E2相关因子）的核转位以及随后诱导GSTA1抗氧化反应元件（ARE）介导的GST活性。磷脂酰肌醇3 - 激酶途径可能参与Nrf2转位的激活。这些结果首次证明绿原酸可预防环境致癌物诱导的致癌作用，并表明绿原酸的化学预防作用可能是通过上调细胞抗氧化酶以及抑制ROS介导的NF - κB、AP - 1和MAPK激活来实现的。
