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，并对患有这种癌症的患者有益。然而，关于大豆异黄酮的抗癌作用存在矛盾的数据，大豆异黄酮具有抗氧化特性，可以通过多种机制影响癌细胞的细胞增殖和凋亡，包括雌激素受体介导。染料木黄酮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有关。这一建议解决了这样一个假设，即生理浓度的染料木素对前列腺癌细胞的增殖或抑制作用取决于它们的MnSOD基因型和ER-状态，以及氧化应激水平。为了验证这一假设，我们将确定染料木黄酮如何在受控的氧化应激环境中作用于具有不同MnSOD变体和ER-<$表达的前列腺癌细胞，具体目的如下：（1）确定ER-<$表达对生理染料木黄酮浓度对细胞增殖和凋亡的影响。将在具有特定MnSOD基因型的细胞中的受控ROS环境中使用生理浓度的染料木黄酮。(2)确定MnSOD基因型对染料木素对表达不同MnSOD变体的前列腺癌细胞的细胞增殖和凋亡的影响，同时控制其ER-状态和ROS环境。(3)确定染料木黄酮在不同活性氧（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-β状态和MnSOD基因型。该提案的结果将为R 01应用提供初步数据，用于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，重点是将染料木素的潜在益处与可能的危害进行对比的非线性剂量-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.