Effects of SOD2 genotype, oxidative stress, ER??, and genistein on prostate cance

SOD2 基因型、氧化应激、ER?? 和金雀异黄酮对前列腺癌的影响

• 批准号: 8115621
• 负责人: MAARTEN C BOSLAND
• 金额: $ 7.85万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-04 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115621
• 关键词: Address; Adverse effects; Affect; Affinity; Animal Model; Antioxidants; Apoptosis; Asians; Behavior; Belief; Binding; Breast Cancer Cell; Cancer Patient; Cell Proliferation; Cells; Chemopreventive Agent; Conflict (Psychology); Consumption; Country; DNA Binding; Data; Development; Dose; Environment; Enzymes; Equilibrium; Estrogen Receptors; Ethanol; Exposure to; Free Radical Scavenging; Genes; Genetic Polymorphism; Genistein; Genotype; Growth; Growth Factor Receptors; Human; Hydrogen Peroxide; In Vitro; Intake; Investigation; Isoflavones; Knowledge; Literature; Malignant Neoplasms; Malignant neoplasm of prostate; Manganese Superoxide Dismutase; Mediation; Meta-Analysis; Monitor; Output; Oxidation-Reduction; Oxidative Stress; Oxidoreductase; Oxygen; Pathway interactions; Patients; Physiological; Population; Property; Prostate; Reactive Oxygen Species; Research; Risk; SOD2 gene; Stress; Superoxide Dismutase; Testing; Therapeutic; Topoisomerase II; Tyrosine Kinase Inhibitor; Up-Regulation; Variant; Vitamin K 3; alanylalanine; angiogenesis; cancer cell; cancer risk; carcinogenesis; catalase; cell growth; glutathione peroxidase; high risk; malignant breast neoplasm; mouse model; prevent; prostate carcinogenesis; response; soy; soy protein isolate; survivorship; valyl-valyl-valine; valylvaline

DESCRIPTION (provided by applicant): Soy consumption may prevent prostate cancer and be beneficial for patients with this cancer. However, there are contradictory data on the anticancer effects of the soy isoflavone genistein, which has antioxidant properties and can affect cell proliferation and apoptosis of cancer cells through multiple mechanisms, including estrogen receptor-¿ mediation. Genistein also affects the expression of the manganese superoxide dismutase (MnSOD) gene and polymorphisms in this gene are related to risk of prostate cancer. This proposal addresses the hypothesis that the proliferative or inhibitory effects of physiological concentrations of genistein on prostate cancer cells are dependent on their MnSOD genotype and ER-¿ status, as well as on oxidative stress levels. To test this hypothesis, we will determine how genistein acts on prostate cancer cells with different MnSOD variants and ER-¿ expression in a controlled oxidative stress environment with these Specific Aims: (1) Determine the influence of ER-¿ expression on the effects of physiological genistein concentrations on cell proliferation and apoptosis. Physiological concentrations of genistein will be used in controlled ROS environments in cells with specific MnSOD genotypes. (2) Determine the influence of MnSOD genotype on the effects of genistein on cell proliferation and apoptosis of prostate cancer cells expressing different MnSOD variants, while controlling their ER-¿ status and the ROS environment. (3) Determine the effects of genistein on prostate cancer cell proliferation and apoptosis at varying input levels of reactive oxygen species (O2.-), while controlling ER-¿ status and MnSOD genotype. The results of this proposal will provide preliminary data for an R01 application for further studies in animal models relevant to soy consumption in therapeutic and chemopreventive settings with a focus on non-linear dose-response relationships contrasting potential benefit with possible harm of genistein.

描述（由申请人提供）： 食用大豆可以预防前列腺癌，并对患有这种癌症的患者有益。然而，关于大豆异黄酮染料木黄酮的抗癌作用存在矛盾的数据，它具有抗氧化特性，可以通过多种机制（包括雌激素受体介导）影响癌细胞的细胞增殖和凋亡。金雀异黄素还影响锰超氧化物歧化酶 (MnSOD) 基因的表达，该基因的多态性与前列腺癌的风险相关。该提案提出了这样的假设：生理浓度的金雀异黄素对前列腺癌细胞的增殖或抑制作用取决于其 MnSOD 基因型和 ER-¿ 状态，以及氧化应激水平。为了检验这一假设，我们将确定金雀异黄素如何在受控氧化应激环境中作用于具有不同 MnSOD 变体和 ER-¿ 表达的前列腺癌细胞，具体目标如下： (1) 确定 ER-¿ 表达对生理金雀异黄素浓度对细胞增殖和凋亡的影响。生理浓度的金雀异黄素将用于具有特定 MnSOD 基因型的细胞中受控的 ROS 环境。 (2)确定MnSOD基因型对金雀异黄酮对表达不同MnSOD变体的前列腺癌细胞增殖和凋亡的影响，同时控制其ER-¿状态和ROS环境。 (3) 确定金雀异黄素在不同活性氧 (O2.-) 输入水平下对前列腺癌细胞增殖和凋亡的影响，同时控制 ER-¿ 状态和 MnSOD 基因型。该提案的结果将为 R01 申请提供初步数据，以便在治疗和化学预防环境中与大豆消费相关的动物模型中进行进一步研究，重点是非线性剂量反应关系，对比染料木黄酮的潜在益处和可能危害。