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Prx1 in malignant progression of prostate cancer

Prx1在前列腺癌恶性进展中的作用

基本信息

批准号：
7579045
负责人：
CANDACE S JOHNSON
金额：
$ 31.11万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
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/7579045
关键词：
Address Affect Androgen Receptor Androgens Antioxidants Apoptosis Base Sequence Binding Biological Biological Assay Blood Vessels Cancer Etiology Cell Culture System Cell Hypoxia Cell Line Cell Proliferation Cell Survival Cells Cessation of life Chromatin Chronic Clinical Cloning Data Deletion Mutagenesis Deoxyribonuclease I Development Dimerization EMSA Elements Employee Strikes Environment Family Gene Targeting Generations Genes Gleason Grade for Prostate Cancer Human Hypoxia In Vitro Knowledge Laboratories Ligand Binding Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Mediating Messenger RNA Metastatic Prostate Cancer Microelectrodes Molecular Molecular Profiling Monitor Neoplasm Metastasis Nuclear Nucleic Acid Regulatory Sequences Outcome Oxidation-Reduction Oxidative Stress PC3 cell line Pattern Phenotype Printing Prostate Prostate Cancer therapy Prostate-Specific Antigen Protein Family Proteins Proteome Proteomics Reactive Oxygen Species Receptor Activation Regulation Research Research Personnel Resistance Role Second Primary Cancers Signaling Molecule Stress Sulfhydryl Compounds Testing Therapeutic Time Tissues Transcriptional Regulation base cancer cell cancer therapy chromatin immunoprecipitation clinically significant deprivation design foot human tissue in vitro activity in vivo mRNA Expression member men novel novel therapeutic intervention oxidation oxidative damage peroxiredoxin pressure prognostic indicator programs promoter receptor binding research study response sound transcription factor tumor tumor growth tumor progression

项目摘要

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.

前列腺癌是最常见的非皮肤癌，是#年癌症死亡的第二大原因。美国的男人。最近的研究表明，前列腺癌细胞在慢性或短暂的低氧中生长。微环境。肿瘤缺氧的程度与不良的临床结果之间的相关性也被认为是演示了。最近，前列腺癌治疗的最常见形式--雄激素剥夺它本身被证明会在前列腺癌中产生一过性缺氧状态。两个高度同源的成员过氧化还蛋白家族，Prx1和Prx2，已被证明影响细胞的增殖/凋亡和增加癌细胞的抗应激能力。然而，Prx在人类癌症中的表达及其影响关于癌症治疗的研究，以及它们在癌症中表达的调控基础还没有被研究过。因为 PI最近表示，可以预测这些Prx对前列腺癌有重大影响前列腺癌中PRX1/2的研究本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研究。中所作的观察 PI的实验室使我们假设PRX1具有独特的功能和调节机制人类前列腺癌对其恶性进展有显著影响。我们的初步数据描述了这里为这一预测提供了令人信服的支持。假设缺氧诱导的肿瘤氧化应激通过以下途径上调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PRX1的结构性上调。它是还假设这些细胞中PRX1的升高为它们提供了侵袭性的生存表型，在部分通过直接减少ROS和氧化损伤，也通过增加前列腺特异性抗原(PSA)。雄激素受体(AR)的表达和活性。进一步假设PRX1的功能是由其控制氧化还原敏感分子的氧化/功能的能力所介导，而氧化还原敏感分子反过来又有助于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AIM 1，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活性对低氧反应中的新作用。在……里面目标3，我们将确定重要的氧化还原敏感的靶/效应分子，它们介导PRX1的功能促进前列腺癌的恶性进展。拟议研究的目标是定义 Prx1在前列腺癌缺氧反应中的作用及其潜在的调控机制。这研究还将为阐明Prx1在前列腺癌中的作用提供可靠的科学基础。能够开发新的预后/治疗方法，以抑制其恶性进展。