HYPOXIA AND PRX1 IN FINASTERIDE AND SELENIUM INTERVENTION OF PROSTATE CANCER

非那雄胺和硒干预前列腺癌中的缺氧和 PRX1

• 批准号: 8135361
• 负责人: YOUNG-MEE PARK
• 金额: $ 31.04万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8135361
• 关键词: Affect; Androgen Receptor; Apoptosis; Apoptotic; Basement membrane; Biological; Blood Vessels; Blood flow; Cancer Control; Cell Culture System; Cell Survival; Cells; Clonal Expansion; Development; Diffusion; Family; Finasteride; Human; Hypoxia; In Vitro; Intervention; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Molecular; Oxidation-Reduction; Oxygen; Partial Pressure; Phenotype; Population; Preventive; Proliferating; Prostate; Protein Family; Proteins; Receptor Signaling; Regulation; Resistance; Selenium; Shunt Device; Signal Transduction; Stress; Testing; Time; Tumor Oxygenation; Up-Regulation; Xenograft Model; base; cancer cell; human tissue; knock-down; member; novel; oxidative damage; pressure; receptor function; response; sound; tissue oxygenation; transcription factor; treatment response; tumor

Hypoxia is a key regulatory microenvironmental factor capable of influencing tumor development and progression. Hypoxia is usually considered a global phenomenon, defined as an overall reduced oxygen availability or partial pressure below critical levels. Tumor vasculature, however, is architecturally and functionally abnormal. The tissue oxygenation/blood flow within a tumor is dynamically changing and heterogeneous at the microenvironmental level. Hypoxia has been proposed to functions as a microenvironmental pressure to select for a fraction of hypoxia-resistant cancer cells with an increased ability to survive and progress. Peroxiredoxins(Prxs) are a newly described family of redox-controlling proteins. Two highly homologous members of this protein family, Prx1 and Prx2, have been shown to affect cell survival and increase stress resistance. However, little is known about the effects of Prx elevation in human cancers, their influence on malignant progression and treatment response, or the regulatory mechanisms. Our preliminary studies provide compelling evidences to support the functional relevance of hypoxiaand Prx1 (but not Prx2) in enhancing the AR function, and suppressing apoptotic signaling. In this study, we will systematically investigate "why"and "how" Prx1 is elevate in prostate cancer cells at the microenvironmentallevel, and study the effect of tissue oxygenation status and Prx1level in modifying the cancer control efficacy of finasteride and selenium. We hypothesize that dynamic changes of tissue oxygenation up-regulate Prx1 expression via redox-sensitive transcription factors, and the dysregulated activation of these transcription factors leads to Prx1 elevation in a subset of prostate cells within a tumor. We also hypothesize that elevated Prx1 confers an aggressive survival phenotype to cells by enhancing AR activity, and reducing oxidative damage and apoptosis. We correspondingly hypothesize that inhibition of Prx1 will increase the AR signaling suppressive and cancer control efficacy of finasteride and selenium. In order to test these hypotheses, four specific aims are proposed. In Aim 1, we will define the molecular basis of Prx1 up-regulation in prostate cancer cells. In Aim 2, we will elucidate the mechanisms whereby Prx1 enhances AR function. In Aim 3 and Aim 4, we will systematically investigate whether and how Prx1 modifies the cancer control efficacy of finasteride and selenium in the context of a hypoxic tumor microenvironment. These studies will provide a sound scientific basis upon which the regulation and function of Prx1 can be elucidated in prostate cancer, enabling the development of novel preventive approaches to inhibit its malignant progression.

缺氧是能够影响肿瘤发展和的关键调节性微环境因素 进展。缺氧通常被认为是一种全球现象，被定义为总体降低氧气 可用性或低于临界水平的部分压力。然而，肿瘤脉管系统在建筑上是 功能异常。肿瘤内的组织氧合/血流正在动态变化，并且 微环境层的异质。已经提出缺氧作为一个 微环境压力以选择能力增加的低氧抗癌细胞的一部分 生存和进步。过氧蛋白（PRX）是一个新描述的氧化还原控制蛋白家族。二 该蛋白质家族PRX1和PRX2的高度同源成员已被证明会影响细胞存活和 增加压力抗性。但是，对人类癌症的PRX升高的影响知之甚少 对恶性进展和治疗反应的影响或调节机制。我们的初步 研究提供了令人信服的证据，以支持低氧和PRX1（而不是PRX2）的功能相关性 增强AR功能并抑制凋亡信号传导。在这项研究中，我们将系统地 研究微环境级别的前列腺癌细胞中的“为什么”和“如何升高”，并研究 组织氧合状态和PRX1Level在修饰非那雄胺和 硒。我们假设组织氧合的动态变化通过 氧化还原敏感的转录因子，这些转录因子的失调激活导致 肿瘤中前列腺细胞子集中的PRX1升高。我们还假设升高的prx1赋予了 通过增强AR活性并减少氧化损伤和 凋亡。我们相应地假设抑制PRX1会增加AR信号抑制 和癌症控制癌症和硒的功效。为了检验这些假设，四个具体目标 提出了。在AIM 1中，我们将定义前列腺癌细胞中PRX1上调的分子基础。在 AIM 2，我们将阐明PRX1增强AR功能的机制。在AIM 3和AIM 4中，我们将 系统地研究PRX1是否修改了非那雄胺的癌症控制功效和 在低氧肿瘤微环境的背景下硒。这些研究将提供一个合理的科学 可以在前列腺癌中阐明PRX1的调节和功能的基础，从而使能够 开发新的预防方法来抑制其恶性进展。