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：
7343181
负责人：
CANDACE S JOHNSON
金额：
$ 30.71万
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/7343181
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 Depth Development Dimerization EMSA Elements Elevation 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 Personal Satisfaction 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 vivo mRNA Expression member men novel novel therapeutics oxidation peroxiredoxin pressure prognostic 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，也是癌症死亡的第二大原因美国的男性。最近的研究表明，前列腺癌细胞在慢性或短暂的缺氧条件下生长微环境。肿瘤缺氧程度与不良临床结果之间也存在相关性证明了。最近，雄激素剥夺是前列腺癌最常见的治疗形式。它本身会在前列腺癌中产生短暂的缺氧状态。两个高度同源的成员过氧化还原蛋白家族 Prx1 和 Prx2 已被证明会影响细胞增殖/凋亡并增加癌细胞的应激抵抗力。然而，Prx 表达在人类癌症中的作用及其影响其在癌症治疗中的作用及其在癌症中表达的调控基础尚未得到研究。因为 PI 最近表示，这些 Prxs 预计会对前列腺癌产生重大影响 Prx1/2 在前列腺癌中的研究。本申请中提出的研究源于我们最近的 Prx1/2 在人类前列腺癌细胞和组织中的调节和功能的研究。所作的观察 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：人类前列腺癌，显着影响其恶性进展。我们的初步数据描述在此为这一预测提供了令人信服的支持。据推测，缺氧诱导的肿瘤氧化应激通过以下方式上调 Prx1 表达：激活氧化还原敏感的转录因子和信号分子，并且失调这些调节成分的激活导致一部分癌细胞中 Prx1 的组成性升高。这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，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的功能是通过其控制氧化还原敏感分子的氧化/功能的能力介导，而氧化还原敏感分子又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。瞄准 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 在缺氧反应中调节 PSA 表达和 AR 活性的新作用。在目标 3，我们将鉴定介导 Prx1 功能的重要氧化还原敏感靶标/效应分子促进前列腺癌恶性进展。拟议研究的目的是定义 Prxl 在前列腺癌缺氧反应中的作用及其相关的潜在调节机制。这研究还将为阐明 Prxl 在前列腺癌中的作用提供合理的科学基础，能够开发新的预后/治疗方法来抑制其恶性进展。