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

描述（由申请人提供）：转录因子Nrf 2通过上调编码抗氧化酶、解毒酶、异生物质转运蛋白和应激反应蛋白的抗氧化反应元件（ARE）携带基因，成为细胞保护机制的主要调节因子。最近，越来越多的证据表明Nrf 2在癌症中具有双重功能。(i)在正常细胞中，当Nrf 2-Keap 1轴完整且Nrf 2的基础水平较低时，化学预防化合物对Nrf 2的瞬时激活赋予对环境毒素和致癌物的保护。(ii)在某些癌细胞系中，Nrf 2的组成性激活创造了有利于癌细胞存活的环境。此外，Nrf 2有助于化学抗性，并且Nrf 2途径的抑制增强癌症治疗的功效。砷（As）是一种人类致癌物，可导致皮肤、肺和膀胱肿瘤。世界各地的大量人口通过受污染的饮用水接触砷，这对人类健康构成了重大挑战。然而，一个足够的啮齿动物模型来研究砷的致癌性仍然缺乏。NIH ES 015010的这种竞争性更新利用了砷在自噬中的一种以前未被认识到的作用，导致Nrf 2的长期激活，这是在上一个资助期发现的。我们推测砷介导的致癌性与其解除自噬途径调节的能力有关。我们认为，典型的Nrf 2诱导剂可以减轻这种影响，因此，可以用作化学预防剂，以抵消砷的破坏作用。提出了以下三个目的：目的1（体外）：阐明砷通过自噬失调（延长Nrf 2的激活）诱导Nrf 2的新机制。目标2（离体）：使用可移植的同基因小鼠肺癌模型确定Nrf 2在砷介导的自噬体形成和致癌性中的作用。目的3（体内）：验证本工作的生物学和药理学相关性。从这个提议中，我们将（i）获得砷如何解除自噬调节的新机制，（ii）证实自噬调节和砷致瘤性之间的关联，（iii）为砷致癌性研究提供新的生物标志物和敏感的动物模型，以及（iv）证明使用典型Nrf 2激活剂靶向Nrf 2途径以对抗砷的潜在翻译影响-诱发毒性和致癌性。此外，开发的同基因小鼠肺癌模型对于研究其他致癌物的科学界将是非常宝贵的。

DESCRIPTION (provided by applicant): The transcription factor, Nrf2, has emerged as the master regulator of a cellular protective mechanism by upregulating antioxidant response element (ARE)- bearing genes encoding antioxidant enzymes, detoxifying enzymes, xenobiotic transporters, and stress response proteins. Very recently, mounting evidence points to the dual function of Nrf2 in cancer. (i) In normal cells when the Nrf2- Keap1 axis is intact and basal level of Nrf2 are low, transient activation of Nrf2 by chemopreventive compounds confers protection against environmental toxins and carcinogens. (ii) In certain cancer cell lines, constitutive activation of Nrf2 creates an environment conducive for cancer cell survival. Moreover, Nrf2 contributes to chemoresistance and inhibition of the Nrf2 pathway enhances the efficacy of cancer treatments. Arsenic (As) is a human carcinogen, which causes tumors in the skin, lung and bladder. Large populations around the world are exposed to arsenic through contaminated drinking water, which imposes a major challenge to human health. However, a sufficient rodent model to study arsenic-carcinogenicity is still lacking. This competing renewal of NIH ES015010 takes advantage of a previously unrecognized role of arsenic in autophagy leading to prolonged activation of Nrf2, which was uncovered during the last funding period. We hypothesize that arsenic-mediated carcinogenicity is associated with its ability to deregulate the autophagic pathway. We believe that canonical Nrf2 inducers can alleviate this effect and thus, can be used as chemopreventive agents to counteract the damaging effects of arsenic. The following three aims are proposed: Aim 1 (in vitro): Elucidate a novel mechanism of Nrf2 induction by arsenic through deregulation of autophagy (prolonged activation of Nrf2). Aim 2 (ex vivo): Determine the role of Nrf2 in arsenic-mediated autophagosome formation and carcinogenicity using a transplantable syngeneic mouse lung cancer model. Aim 3 (in vivo): Validate the biological and pharmacological relevancy of this work. From this proposal we will (i) gain novel mechanistic insight of how arsenic deregulates autophagy, (ii) confirm the association between deregulation of autophagy and tumorigenicity of arsenic, (iii) provide new biomarkers and a sensitive animal model for arsenic carcinogenicity studies and (iv) demonstrate the potential translational impact of targeting the Nrf2 pathway using canonical Nrf2 activators to combat arsenic-induced toxicity and carcinogenicity. In addition, the syngeneic mouse lung cancer model developed will be invaluable for scientific communities studying other carcinogens.