Oxidative stress, Cr(VI) carcinogenesis, and prevention

氧化应激、Cr(VI) 致癌作用及预防

• 批准号: 8912686
• 负责人: Xianglin Shi
• 金额: $ 33.84万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8912686
• 关键词: 2 year old; Adult; Animal Model; Animals; Antioxidants; Apoptosis; Apoptotic; BCL2 gene; Binding; Breeding; Cell Death; Cells; Chemopreventive Agent; Chronic; Data; Development; Diet; Elements; Environmental Carcinogens; Epidemiologic Studies; Epithelial; Event; Exhibits; Exposure to; Female; Gene Expression; Gene Targeting; Generations; Genes; Life; Literature; Lung; Luteolin; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Metal exposure; Molecular; Mus; Nutritional; Occupational; Oncogenic; Oxidative Stress; Pathway interactions; Pregnancy; Premalignant; Prevention; Prevention strategy; Property; Proteins; Reactive Oxygen Species; Resistance; Role; Signal Pathway; Signal Transduction; Source; Staging; Stress; Superoxide Dismutase; Time; Tumor Tissue; Tumorigenicity; Up-Regulation; angiogenesis; antioxidant enzyme; cancer cell; carcinogenesis; carcinogenicity; cell transformation; chromium hexavalent ion; combat; drinking water; exposed human population; in vivo; insight; male; malignant state; novel; offspring; pregnant; prevent; promoter; public health relevance; tumor; tumorigenesis

 DESCRIPTION (provided by applicant): Cr(VI) is well known environmental carcinogen. Its mechanism of action or prevention remains to be investigated. Our preliminary studies have shown that exposure of human bronchial epithelial (BEAS-2B) cells to Cr(VI) generates reactive oxygen species (ROS) which are responsible for Cr(VI)-induced cell transformation. After transformation, these cells exhibit constitutive expressions of Nrf2 and its target antioxidant proteins, resulting in decreased ROS generation. The constitutive expression of Nrf2 activates Bcl-2 through binding of Nrf2 to antioxidant responsive element (ARE) of Bcl-2 gene promoter, leading to increased survival and tumorigenicity of these transformed cells. These preliminary studies indicate that in non-transformed cells activation of Nrf2 may decrease ROS generation, thus inhibit Cr(VI)-induced cell transformation. In contrast, in Cr(VI)-transformed cells inactivation of constitutive expression of Nrf2 may decrease Bcl-2 and increase ROS, leading to inhibitions of survival and tumorigenicity of transformed cells. We have screened various natural compounds attempting to select those with two properties: (a) to activate Nrf2 and decrease ROS in non- transformed cells to prevent Cr(VI)-induced cell transformation and (b) to inhibit constitutive expression of Nrf2 and enhance ROS and apoptosis in Cr(VI)-transformed cells to prevent tumorigenesis. We have found that luteolin, a natural compound, has such dual properties. The central hypothesis is that luteolin protects Cr(VI)- induced carcinogenesis both by inducing transient activation of Nrf2 in non-transformed cells, resulting in inhibition of Cr(VI-induced cell transformation and by inactivating constitutive expression of Nrf2 in Cr(VI)- transformed cells, resulting in inhibitions of survival and tumorigenesi of Cr(VI)-transformed cell and angiogenesis. Aim 1 will study prevention of luteolin against Cr(VI)-induced cell transformation. We will study luteolin-induced activations of Nrf2 and its target antioxidant genes, and decreases of Cr(VI)-generated ROS. The integration of these molecular events is likely to be responsible for protection of luteolin against Cr(VI)- induced cells transformation. Aim 2 will demonstrate that in Cr(VI)-transformed cells luteolin is able to inhibit constitutive expressions of Nrf2, increase ROS level, and decrease survival and tumorigenicity of Cr(VI)- transformed cells. The protection of luteolin against Cr(VI)-induced angiogenesis in animal exposed to Cr(VI) via drinking water will also be investigated. Aim 3 will investigate protection o luteolin against Cr(VI)-induced carcinogenicity in CD1 mice using a recently established animal model of "whole-life" chronic metal exposure. The animals will be exposed to Cr(VI) in the presence and absence of luteolin via drinking water in the whole life time from breeding to adulthood. The roles of Nrf2 and its key target will be studied. Tumors will be assessed in the offspring up to 2 years of adulthood. The proposed study will not only gain novel mechanistic insight in Cr(VI) carcinogenesis, but also have potential translational impact of using chemopreventive compounds targeting Nrf2 signaling pathway to combat Cr(VI)-induced carcinogenicity.

 描述（申请人提供）： Cr(VI) 是众所周知的环境致癌物质。其作用或预防机制仍有待研究。我们的初步研究表明，人支气管上皮 (BEAS-2B) 细胞暴露于 Cr(VI) 会产生活性氧 (ROS)，从而导致 Cr(VI) 诱导的细胞转化。转化后，这些细胞表现出 Nrf2 及其靶抗氧化蛋白的组成型表达，导致 ROS 生成减少。 Nrf2 的组成型表达通过 Nrf2 与 Bcl-2 基因启动子的抗氧化反应元件 (ARE) 结合来激活 Bcl-2，从而提高这些转化细胞的存活率和致瘤性。这些初步研究表明，在非转化细胞中，Nrf2 的激活可能会减少 ROS 的产生，从而抑制 Cr(VI) 诱导的细胞转化。相反，在 Cr(VI) 转化细胞中，Nrf2 组成型表达失活可能会减少 Bcl-2 并增加 ROS，从而抑制转化细胞的存活和致瘤性。我们筛选了各种天然化合物，试图选择具有两种特性的化合物：（a）激活Nrf2并减少非转化细胞中的ROS以防止Cr（VI）诱导的细胞转化；（b）抑制Nrf2的组成型表达并增强Cr（VI）转化细胞中的ROS和细胞凋亡以防止肿瘤发生。我们发现木犀草素这种天然化合物具有这样的双重特性。中心假设是，木犀草素通过诱导非转化细胞中 Nrf2 的短暂激活，从而抑制 Cr(VI 诱导的细胞转化) 和灭活 Cr(VI) 转化细胞中 Nrf2 的组成型表达，从而抑制细胞的存活和肿瘤发生，从而保护 Cr(VI) 诱导的癌发生。 Cr(VI) 转化细胞和血管生成。目标 1 将研究木犀草素对 Cr(VI) 诱导的细胞转化的预防作用。我们将研究木犀草素诱导的 Nrf2 及其靶抗氧化基因的激活，以及 Cr(VI) 产生的 ROS 的减少。这些分子事件的整合可能是木犀草素保护免受 Cr(VI) 诱导的细胞影响的原因 转变。目标 2 将证明，在 Cr(VI) 转化细胞中，木犀草素能够抑制 Nrf2 的组成型表达，增加 ROS 水平，并降低 Cr(VI) 转化细胞的存活率和致瘤性。还将研究木犀草素对通过饮用水接触 Cr(VI) 的动物免受 Cr(VI) 诱导的血管生成的保护作用。目标 3 将研究木犀草素的保护作用 使用最近建立的“一生”慢性金属暴露动物模型来对抗 Cr(VI) 诱导的 CD1 小鼠致癌性。从繁殖到成年，动物在整个生命周期中都会通过饮用水接触到存在或不存在木犀草素的 Cr(VI)。将研究 Nrf2 的作用及其关键靶标。将对后代直至成年 2 岁的肿瘤进行评估。 拟议的研究不仅将获得 Cr(VI) 致癌作用的新机制见解，而且还具有使用针对 Nrf2 信号通路的化学预防化合物对抗 Cr(VI) 诱导的致癌性的潜在转化影响。