摘要
Chemical insults, whether of endogenous or exogenous origins, play major roles in the etiopathogenesis of many cancers. As such, strategies to blunt their formation and limit their damage to biomolecules are a central aspect of chemoprevention. Cellular defenses against such insults are regulated in part by the transcription factor Nrf2. Nrf2, in turn, regulates gene expression through interactions with the ARE (antioxidant-response-element) found in the promoter regions of many cytoprotective genes. Under basal conditions, Nrf2 is tethered in the cytoplasm to an actin binding protein Keap1. Pharmacological and food-derived agents such as dithiolethiones and isothiocyanates trigger the release of Nrf2 from Keap1, allowing it to translocate into the nucleus and stimulate gene transcription. Studies using nrf2-deficient mice have revealed that Nrf2 regulates basal and inducible expression of multiple categories of genes, including xenobiotic-metabolizing enzymes, antioxidant enzymes, molecular chaperones/stress response proteins, as well as proteasome subunits, that collectively reflect the complex and important role Nrf2 plays in the cellular defense against carcinogens. Nrf2 knockout mice are greatly predisposed to chemical-induced DNA damage and exhibit higher susceptibility towards cancer development in several models of chemical carcinogenesis. Nrf2 also mediates protection against oxidative stress and influences inflammatory processes, both of which contribute to carcinogenesis. Observations that nrf2-deficient mice are refractory to the protective actions of some chemopreventive agents highlight the importance of the Keap1–Nrf2–ARE signaling pathway as a molecular target for prevention.
摘要译文
化学损伤，无论是内源性还是外源性，在许多癌症的发病机理中起主要作用。因此，钝化其形成并限制其对生物分子的损害的策略是化学预防的中心方面。针对这种损害的细胞防御部分由转录因子Nrf2调节。 Nrf2，反过来，通过与许多细胞保护性基因的启动子区域中发现的ARE（抗氧化剂 - 反应元件）的相互作用来调节基因表达。在基础条件下，Nrf2在细胞质中被束缚到肌动蛋白结合蛋白Keap1上。药理学和食品衍生物如二硫苏糖醇和异硫氰酸酯引发Keap1释放Nrf2，使其易位至细胞核并刺激基因转录。使用nrf2缺陷型小鼠的研究揭示了Nrf2调节多种基因的基础和可诱导表达，包括异生素代谢酶，抗氧化酶，分子伴侣/应激反应蛋白以及蛋白酶体亚基，这些共同反映了Nrf2在对致癌物的细胞防御中发挥的复杂而重要的作用。Nrf2基因敲除小鼠极易倾向于化学诱导的DNA损伤，并在几种化学致癌作用模型中表现出对癌症发展的更高易感性。Nrf2也介导保护免受氧化应激和影响炎症过程，两者都有助于癌变。nrf2缺陷型小鼠难以对某些化学预防剂的保护作用强调了Keap1-Nrf2-ARE信号通路作为预防分子靶标的重要性。
XiangYu[a];ThomasKensler[a][b];. Nrf2 as a target for cancer chemoprevention[J]. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 2005,591(1-2): 93-102