Prx1 in malignant progression of prostate cancer

描述(申请人提供)：前列腺癌是美国最常见的非皮肤癌，也是男性癌症死亡的第二大原因。最近的研究表明，前列腺癌细胞在慢性或短暂的低氧微环境中生长。肿瘤缺氧的程度和不良的临床结果之间的相关性也已被证明。最近，前列腺癌治疗的最常见形式--雄激素剥夺--本身就被证明会在前列腺癌中产生一过性缺氧状态。过氧化还蛋白家族中两个高度同源的成员，Prx1和Prx2，已被证明影响细胞的增殖/凋亡，并提高癌细胞的抗应激能力。然而，PRX在人类癌症中的表达及其对癌症治疗的影响，以及它们在癌症中表达的调控基础还没有被研究。由于可以预测这些Prx对前列腺癌有显著影响，研究人员最近对前列腺癌中的Prx1/2进行了研究。本申请中提出的研究源于我们最近对PRX1/2在人前列腺癌细胞和组织中的调节和功能的研究。在PI的实验室中所做的观察使我们假设PRX1在人类前列腺癌中具有独特的功能和调节机制，显著影响其恶性进展。我们在这里描述的初步数据为这一预测提供了令人信服的支持。有人假设，低氧诱导的肿瘤氧化应激通过激活氧化还原敏感的转录因子和信号分子上调PRX1的表达，这些调节成分的异常激活导致肿瘤细胞亚群中PRX1的结构性升高。还假设，这些细胞中PRX1的升高为它们提供了侵袭性的生存表型，部分是通过直接减少ROS和氧化损伤，也通过增加前列腺特异性抗原(PSA)的表达和雄激素受体(AR)的活性。进一步的假设是，PRX1的功能是通过它控制氧化还原敏感分子的氧化/功能而介导的，而氧化还原敏感分子反过来又促进前列腺癌的恶性进展。为了检验这些假说，本文提出了三个具体目标。在目标1中，我们将建立PRX1在人前列腺癌细胞中上调的分子基础。在目标2中，我们将确定PRX1在前列腺癌细胞恶性进展中的功能意义。特别是，我们将研究PRX1在调节PSA表达和AR活性方面对低氧反应的新作用。在目标3中，我们将识别重要的氧化还原敏感靶/效应分子，它们介导PRX1的功能，促进前列腺癌的恶性进展。本研究的目的是明确PRX1在前列腺癌缺氧反应中的作用及其潜在的调控机制。这项研究还将为阐明PRX1在前列腺癌中的作用提供可靠的科学基础，使开发新的预后/治疗方法来抑制前列腺癌的恶性进展。

DESCRIPTION (provided by applicant): 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 investigator 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 that the 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/effecter molecules that mediate the Prx1 functions to promote malignant progression of prostate cancer. The objective of the proposed research is to define the role of Prx1 in hypoxia-response of prostate cancer and the underlying regulatory mechanisms involved. This study will also provide a sound scientific basis upon which the role of Prx1 can be elucidated in prostate cancer, enabling the development of novel prognostic/therapeutic approaches to inhibit its malignant progression.