Prx1 in malignant progression of prostate cancer

Prx1在前列腺癌恶性进展中的作用

• 批准号: 7101594
• 负责人: YOUNG-MEE PARK
• 金额: $ 30.83万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-05 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7101594
• 关键词: human; hypoxia; neoplasm /cancer; neoplastic cell; prostate neoplasms; role

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.

描述（由申请人提供）：前列腺癌是美国男性最常见的非直率癌症，也是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。还已经证明了肿瘤缺氧程度与临床不良结果之间的相关性。最近，雄激素剥夺是前列腺癌治疗的最常见形式，它本身被证明会在前列腺癌中产生短暂性缺氧状态。已证明过氧化物蛋白蛋白家族的两个高度同源成员PRX1和PRX2会影响细胞的增殖/凋亡，并增加癌细胞中的应激性。但是，尚未研究PRX表达在人类癌症中的影响，对癌症治疗的影响以及其在癌症中表达的调节基础尚未得到研究。由于可以预测这些PRX会对前列腺癌产生重大影响，因此研究者最近在前列腺癌中对PRX1/2进行了研究。该应用中提出的研究源于我们最近对人类前列腺癌细胞和组织中PRX1/2调节和功能的研究。 PI实验室中的观察结果使我们假设PRX1在人类前列腺癌中具有独特的功能和调节机制，从而显着影响其恶性进展。本文所述的我们的初步数据为这一预测提供了令人信服的支持。假设缺氧诱导的肿瘤中的氧化应激通过激活氧化还原敏感的转录因子和信号分子来上调PRX1表达，并且这些调节成分的失调激活导致癌细胞子群中的组成型PRX1升高。还可以假设，这些细胞中的升高PRX1为它们提供了侵略性的生存表型，部分是通过直接减少ROS和氧化损伤，以及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的功能是由控制氧化还原敏感分子的氧化/功能的能力介导的，而氧化还原敏感分子的氧化/功能又导致了前列腺癌的恶性进展。提出了三个特定目标来检验这些假设。在AIM 1中，我们将建立人类前列腺癌细胞中PRX1升高的分子基础。在AIM 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活性响应缺氧方面的新作用。在AIM 3中，我们将确定介导PRX1功能以促进前列腺癌的恶性进展的重要氧化还原敏感靶/效应子分子。拟议的研究的目的是定义PRX1在前列腺癌缺氧反应中的作用以及所涉及的潜在调节机制。这项研究还将提供一个合理的科学依据，可以阐明PRX1在前列腺癌中的作用，从而开发新的预后/治疗方法来抑制其恶性进展。