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

描述(由申请人提供)： 食用大豆可以预防前列腺癌，并有益于前列腺癌患者。然而，大豆异黄酮染料木素的抗癌作用却有相互矛盾的数据，它具有抗氧化特性，可以通过多种机制影响癌细胞的增殖和凋亡，包括雌激素受体介导。金雀异黄素还影响锰超氧化物歧化酶(MnSOD)基因的表达，该基因的多态与前列腺癌的风险有关。这一建议解决了这样的假设，即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它们的MnSOD基因和ER-1状态，以及氧化应激水平。为了验证这一假设，我们将确定金雀异黄素在受控氧化应激环境中如何作用于具有不同MnSOD变异体和ER-？表达的前列腺癌细胞：(1)确定ER-？表达对生理浓度金雀异黄素对细胞增殖和凋亡影响的影响。生理浓度的金雀异黄素将用于具有特定MnSOD基因型的细胞的受控ROS环境中。(2)检测不同MnSOD基因突变对金雀异黄素诱导表达不同MnSOD突变体的前列腺癌细胞增殖和凋亡的影响，同时控制其ER-β状态和ROS环境。(3)检测不同氧自由基(O2.-)输入水平下金雀异黄素对前列腺癌细胞增殖和凋亡的影响，同时控制ER-β状态和MnSOD型。这项建议的结果将为R01的应用提供初步数据，以进一步研究与治疗和化学预防环境中的大豆消费相关的动物模型，重点是对比染料木素的潜在益处和可能危害的非线性剂量-反应关系。

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.