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毒性/致癌的分子机制以及应对污染物的内源性细胞防御系统。受砷污染的饮用水是一种已知的致癌物质，是一个世界性的公共卫生问题。流行病学研究已将砷暴露与人类癌症联系起来，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)来造成细胞损伤，这些ROS甚至参与了肿瘤的启动、促进和发展。虽然砷是一种明确的致癌物，但它没有诱变性，可能通过表观遗传或细胞信号机制诱导恶性转化。真核细胞已经进化出几种防御机制来应对来自环境的压力，其中之一是哺乳动物细胞用来中和ROS和维持细胞氧化还原动态平衡的抗氧化反应。这种抗氧化系统是通过抗氧化剂和第二相解毒基因启动子中的抗氧化反应元件(ARE)序列介导的，这些基因包括谷胱甘肽S转移酶、NAD(P)H苯醌氧化还原酶、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Nrf2控制。ARE-Nrf2-Keap1信号通路被具有抗癌活性的化合物激活，已被明确证明对肿瘤的发生有深远的影响。更重要的是，Nrf2基因敲除小鼠对化学毒物和致癌物表现出更高的敏感性，并且对化学预防化合物的保护作用无效。因此，我们假设ARE-Nrf2-Keap1通路的激活可能作为一种内源性保护系统来对抗砷的毒性和致癌性。以下特定目的旨在进一步阐明NRF2激活对砷诱导的毒性/致瘤性的保护作用的机制。这些知识可以潜在地为科学和医学界服务，我们的目标是创造具有更高特异性和有效性的新型化学预防药物，这将对世界各地的人类健康产生广泛影响。我们建议(1)确定ARE-Nrf2-Keap1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-Nrf2-Keap1通路的分子机制；(3)利用Nrf2基因敲除小鼠模型，确定ARE-Nrf2-Keap1通路在砷诱导的毒性和致癌中的保护作用。

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.