The protective role of Nrf2 in arsenic-induced toxicity and carcinogenicity

描述（由申请人提供）： 我们研究的总体目标是了解环境污染物的毒性/致癌性的分子机制以及科普污染物的内源性细胞防御系统。被砷污染的饮用水是一种已知的致癌物质，是一个全球性的公共卫生问题。流行病学研究表明，砷暴露与人类癌症有关，包括皮肤癌、肝癌、肺癌、肾癌、前列腺癌和膀胱癌。砷还可以通过产生活性氧（ROS）引起细胞损伤，这些活性氧甚至参与肿瘤的发生、促进和进展。虽然砷是一种明确的致癌物，但它不具有致突变性，并可能通过表观遗传或细胞信号传导机制诱导恶性转化。 真核细胞已经进化出几种防御机制来科普来自环境的压力，其中之一是哺乳动物细胞用来中和ROS并维持细胞氧化还原稳态的抗氧化反应。该抗氧化系统通过存在于几种抗氧化剂和II相解毒基因的启动子中的抗氧化反应元件（ARE）序列介导，所述基因包括谷胱甘肽S-转移酶、NAD（P）H醌氧化还原酶、谷氨酰半胱氨酸合成酶和血红素加氧酶。抗氧化反应系统主要由转录因子Nrf 2控制。ARE-Nrf 2-Keap 1信号通路被具有抗癌特性的化合物激活，已被清楚地证明对肿瘤发生具有深远的影响。更重要的是，Nrf 2基因敲除小鼠显示出对化学毒物和致癌物的敏感性增加，并且对化学预防化合物的保护作用难以抵抗。 因此，我们假设ARE-Nrf 2-Keap 1通路的激活作为一种内源性保护系统，对砷诱导的毒性和致癌性。以下具体目的旨在进一步阐明Nrf 2活化在保护砷诱导的毒性/致瘤性中的机制。这些知识可能有助于科学和医学界实现我们的目标，即创造具有更高特异性和有效性的新型化学预防剂，这将对全球人类健康产生广泛影响。本研究拟（1）确定ARE-Nrf 2-Keap 1通路在砷诱导的毒性和致癌性中的保护作用;（2）确定砷激活ARE-Nrf 2-Keap 1通路的分子机制;（3）使用Nrf 2基因敲除小鼠模型确定ARE-Nrf 2-Keap 1通路在砷诱导的毒性和致瘤性中的保护作用。

DESCRIPTION (provided by applicant): The overall goal of our research is to understand the molecular mechanisms of toxicity/carcinogenicity of environmental pollutants and the endogenous cellular defense systems to cope with pollutants. Drinking water contaminated with arsenic, a known carcinogen, is a worldwide public health issue. Epidemiology studies have linked arsenic exposure to human cancers, including skin, liver, lung, kidney, prostate, and bladder cancer. Arsenic can also cause cellular damage through generation of reactive oxygen species (ROS) that are even involved in the initiation, promotion, and progression of tumors. Although arsenic is a well defined carcinogen, it is not mutagenic and induces malignant transformation possibly by an epigenetic or cell signaling mechanism. Eukaryotic cells have evolved several defense mechanisms to cope with stress from the environment, one of which is the antioxidant response utilized by mammalian cells to neutralize ROS and to maintain cellular redox homeostasis. This antioxidant system is mediated through the antioxidant response element (ARE) sequence present in the promoters of several antioxidant and Phase II detoxification genes including glutathione S-transferase, NAD(P)H quinone oxidoreductase, glutamylcysteine synthetase, and heme-oxygenase. The antioxidant response system is mainly controlled by the transcription factor Nrf2. Activated by compounds possessing anti-cancer properties, the ARE-Nrf2-Keap1 signaling pathway has been clearly demonstrated to have profound effects on tumorigenesis. More significantly, Nrf2 knockout mice display increased sensitivity to chemical toxicants and carcinogens and are refractory to the protective actions of chemopreventive compounds. Therefore, we hypothesize that activation of the ARE-Nrf2-Keap1 pathway acts as an endogenous protective system against arsenic-induced toxicity and carcinogenicity. The following specific aims are intended to further elucidate the mechanism of Nrf2-activation in protection from arsenic-induced toxicity/tumorigenicity. This knowledge can potentially serve the scientific and medical community in our objective to create novel chemopreventive agents with increased specificity and efficacy, which will have broad impact on human health worldwide. We propose to (1) determine the protective role of the ARE-Nrf2- Keap1 pathway in arsenic-induced toxicity and carcinogenicity, (2) define the molecular mechanisms of activation of the ARE-Nrf2-Keap1 pathway by arsenic, and (3) define the protective role of the ARE-Nrf2-Keap1 pathway in arsenic-induced toxicity and tumorigenicity using the Nrf2 knockout mouse model.