HYPOXIA AND PRX1 IN FINASTERIDE AND SELENIUM INTERVENTION OF PROSTATE CANCER

缺氧是能够影响肿瘤发展的关键调节微环境因素， 进展缺氧通常被认为是一个全球性的现象，定义为整体减少氧气 可用性或分压低于临界水平。然而，肿瘤脉管系统在结构上是 功能异常肿瘤内的组织氧合/血流动态变化， 在微环境层面上，缺氧被认为是一种 微环境压力来选择一部分耐缺氧的癌细胞， 为了生存和进步。过氧化物酶（Peroxiredoxins，Prxs）是一个新近发现的氧化还原调控蛋白家族。两 该蛋白质家族的高度同源成员Prx 1和Prx 2已显示影响细胞存活， 增加抗压力。然而，关于Prx升高在人类癌症中的作用知之甚少， 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，支持缺氧和Prx 1（而不是Prx 2）在 增强AR功能和抑制凋亡信号。在这项研究中，我们将系统地 在微环境水平上研究Prx 1在前列腺癌细胞中升高的“原因“和“方式”， 组织氧合状态和Prx 1水平在改变非那普利的癌症控制功效中的作用， 硒。我们假设组织氧合的动态变化通过以下途径上调Prx 1的表达： 氧化还原敏感的转录因子，这些转录因子的失调激活导致 肿瘤内前列腺细胞亚群中Prx 1升高。我们还假设Prx 1升高会导致 通过增强AR活性和减少氧化损伤， 凋亡我们相应地假设Prx 1的抑制将增加AR信号抑制， 和硒的抗癌功效。为了验证这些假设，四个具体目标 被提议。在目标1中，我们将定义Prx 1在前列腺癌细胞中上调的分子基础。在 目的2：阐明Prx 1增强AR功能的机制。在目标3和目标4中，我们将 系统地研究Prx 1是否以及如何改变非那肽的癌症控制功效， 硒在缺氧肿瘤微环境中的作用。这些研究将提供一个健全的科学 在此基础上，可以阐明Prx 1在前列腺癌中的调节和功能， 开发新的预防方法来抑制其恶性进展。

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.