Prx1 in malignant progression of prostate cancer

前列腺癌是最常见的非皮肤癌，也是癌症死亡的第二大原因。 男人在美国。最近的研究表明，前列腺癌细胞生长在慢性或短暂的缺氧环境中， 微环境肿瘤缺氧程度和不良临床结果之间的相关性也已被证实。 演示。最近，雄激素剥夺，最常见的前列腺癌治疗形式， 其本身显示在前列腺癌中产生短暂缺氧状态。两个高度同源的成员 过氧化物氧还蛋白家族Prx1和Prx2已显示影响细胞增殖/凋亡，并增加 癌细胞的抗应激能力然而，Prx表达在人类癌症中的作用，它们的影响， 在癌症治疗中的作用，以及它们在癌症中表达的调控基础尚未研究。因为 这些Prxs可以预测对前列腺癌有显著影响，PI最近进行了研究， Prx1/2在前列腺癌中的作用这项申请中提出的研究源于我们最近的 Prx1/2在人前列腺癌细胞和组织中的调节和功能的研究。中的意见 Pi的实验室使我们假设Prx1在以下方面具有独特的功能和调节机制： 人前列腺癌，显著影响其恶性进展。我们的初步数据显示 在此为这一预测提供了有力支持。 据推测，缺氧诱导的氧化应激在肿瘤中上调Prx1的表达， 激活氧化还原敏感的转录因子和信号分子， 这些调节成分的激活导致癌细胞亚群中的组成性Prx1升高。是 还假设这些细胞中Prx1的升高为它们提供了侵袭性存活表型， 部分通过直接减少ROS和氧化损伤，也通过增加前列腺特异性抗原（PSA） 表达和雄激素受体（AR）活性。进一步假设Prx1的功能是 通过其控制氧化还原敏感性分子的氧化/功能的能力介导，氧化还原敏感性分子反过来有助于 前列腺癌的恶性进展。提出了三个具体目标来检验这些假设。在aim中 1，我们将建立人前列腺癌细胞中Prx1升高的分子基础。在目标2中，我们 确定Prx1在前列腺癌细胞恶性进展中的功能意义。我们尤其 将研究Prx1在调节PSA表达和AR活性以应对缺氧中的新作用。在 目的3，我们将确定重要的氧化还原敏感性靶/效应分子介导的Prx1功能， 促进前列腺癌的恶性进展。拟议研究的目的是确定 Prxl在前列腺癌缺氧反应中的作用及其潜在的调节机制。这 这项研究还将为阐明Prxl在前列腺癌中的作用提供可靠的科学依据， 从而能够开发新的预后/治疗方法来抑制其恶性进展。

Prostate cancer is the most common noncutaneous cancer and the second leading cause of cancer death in men in the US. Recent studies demonstrated that prostate cancer cells grow in a chronic or transient hypoxic microenvironment. A correlation between the extent of tumor hypoxia and poor clinical outcome has also been demonstrated. More recently, androgen deprivation, the most common form of prostate cancer therapy, was itself shown to generate a state of transient hypoxia in prostate cancer. Two highly homologous members of the peroxiredoxin protein family, Prx1 and Prx2, have been shown to affect cell proliferation/apoptosis and increase the stress resistance in cancer cells. However, the effects of Prx expression in human cancers, their influence on cancer therapy, and the regulatory basis of their expression in cancer have not been investigated. Because these Prxs can be predicted to have a significant impact on prostate cancer, the PI has recently undertaken studies of Prx1/2 in prostate cancer. The research proposed in this application emanates from our recent studies of Prx1/2 regulation and function in human prostate cancer cells and tissues. The observations made in the Pi's laboratory led us to postulate that Prx1 possesses unique functions and regulatory mechanisms in human prostate cancer that significantly influences its malignant progression. Our preliminary data described herein provide compelling support of this prediction. It is hypothesized that hypoxia-induced oxidative stress in tumors up-regulates Prx1 expression via activating the redox-sensitive transcriptional factors and signaling molecules and that the dysregulated activation of these regulatory components leads to a constitutive Prx1 elevation in a subset of cancer cells. It is also hypothesized thatihe elevated Prx1 in these cells provides them with aggressive survival phenotypes, in part by directly reducing ROS and oxidative damage, and also by increasing prostate specific antigen (PSA) expression and androgen receptor (AR) activity. It is further hypothesized that the functions of Prx1 are mediated by its ability to control the oxidation/function of redox-sensitive molecules that in turn contribute to the malignant progression of prostate cancer. Three Specific Aims are proposed to test these hypotheses. In Aim 1, we will establish the molecular basis for Prx1 elevation in human prostate cancer cells. In Aim 2, we will determine the functional significance of Prx1 in malignant progression of prostate cancer cells. In particular, we will investigate the novel role for Prx1 in regulating PSA expression and AR activity in response to hypoxia. In Aim 3, we will identify important redox-sensitive target/effector molecules that mediate the Prx1 functions to promote malignant progression of prostate cancer. The objective of the proposed research is to define the role ofPrxl in hypoxia-response of prostate cancer and the underlying regulatory mechanisms involved. This study will also provide a soundscientific basis upon which the role ofPrxl canbe elucidatedin prostate cancer, enabling the development of novelprognostic/therapeutic approaches to inhibit its malignant progression.