Regulator of G-protein Signaling (RGS) Proteins in Prostate Cancer

前列腺癌中 G 蛋白信号转导 (RGS) 蛋白的调节因子

基本信息

批准号：
7626813
负责人：
YAPING TU
金额：
$ 24.58万
依托单位：
CREIGHTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7626813
关键词：
Adenovirus Infections Adrenergic Receptor Affect American Amino Acids Androgen Receptor Androgens Biological Biology CWR22Rv1 Cancer Cell Growth Cell Line Cell Proliferation Clinical DMA-methyltransferase Data Deoxycytidine Development Diagnosis Diagnostic Disease Dominant-Negative Mutation Down-Regulation G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Protein Regulators Genes Goals Growth Histone Deacetylase Inhibitor Hormones Human Hypermethylation Immunohistochemistry Knockout Mice Knowledge LNCaP Malignant Neoplasms Malignant neoplasm of prostate Mediating Methods Methylation Mitogen-Activated Protein Kinase 3 Molecular Mutation Nude Mice Outcome PC3 cell line Pharmaceutical Preparations Play Prognostic Marker Prostate Prostatic Neoplasms Proteins RGS Proteins RGS2 gene Receptor Activation Receptor Signaling Regulation Reporting Repression Research Research Design Research Personnel Role Signal Pathway Signal Transduction Specimen Tissues Tumorigenicity Weight Xenograft procedure androgen independent prostate cancer anticancer research cancer cell cell growth design gene repression histone modification human disease in vitro Assay in vivo inhibitor/antagonist member men mutant novel novel marker novel therapeutic intervention outcome forecast overexpression programs promoter protein expression receptor coupling receptor function response tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Aberrant G protein-coupled receptor (GPCR) signaling causes many human diseases including cancer. Regulator of G-protein signaling (RGS) proteins inhibit GPCR signaling. The long-term goal of this application is to elucidate the roles of RGS proteins in tumorigenesis. Prostate cancer is the most common cancer in men and acquisition of androgen independence by prostate cancer is the key problem of prostate cancer progression. Several lines of evidence suggest that androgen-independent activation of androgen receptor (AR) is one of underlying mechanisms. Recent studies demonstrate that hormones acting through G protein-coupled receptors (GPCRs) cause androgen-independent AR activation. We recently reported that RGS2, a member of RGS superfamily, selectively inhibits androgen-independent AR activation by GPCR signaling in prostate cancer cells. Interestingly, RGS2 protein expression was inversely correlated with the androgen-independent cell proliferation in established prostate cancer cell lines. In addition, human prostate cancer specimens had significantly lower levels of RGS2 compared to normal prostate tissues. Thus, we hypothesize that RGS2 functions as a novel regulator of AR signaling and its repression is an important step in prostate tumorigenesis and progression. Specific Aims: 1. To assess the biological importance of RGS2 repression in prostate cancer cells. 2. To determine the molecular mechanism underlying RGS2-mediated inhibition of androgen-independent prostate cancer growth. 3. To elucidate the mechanism underlying RGS2 repression in prostate cancer. Research Design and Methods: We will first examine the effects of altering RGS2 expression on the androgen-independent growth of prostate cancer cells in culture and in castrated athymic nude mice. We will then pinpoint the amino acids of RGS2 critical for its selective inhibition of androgen-independent AR activation and cell growth in prostate cancer cells and identify the AR domains responsible for its regulation by RGS2. Finally, we will combine methylation-specific PCR and immunohistochemistry analysis to investigate whether methylation of the RGS2 gene is responsible for RGS2 repression in prostate cancer. The feasibility of using RGS2 expression and/or RGS2 methylation status as a novel marker for diagnosis and prognosis of prostate cancer will then be evaluated. In addition to methylation, we will also explore whether genetic alterations or histone modifications contribute to RGS2 repression in prostate cancer. Information on the biological importance of RGS2 in the regulation of prostate cancer progression is directly relevant to understanding the biology of prostate cancer. Completion of the proposed studies will not only provide a potential diagnostic and prognosis marker for prostate cancer progression but will also allow the development of novel drugs for the treatment of prostate cancers.

描述（由申请人提供）：异常的 G 蛋白偶联受体 (GPCR) 信号传导导致许多人类疾病，包括癌症。 G 蛋白信号传导 (RGS) 蛋白的调节蛋白抑制 GPCR 信号传导。该应用的长期目标是阐明 RGS 蛋白在肿瘤发生中的作用。前列腺癌是男性最常见的癌症，前列腺癌获得雄激素独立性是前列腺癌进展的关键问题。多项证据表明，雄激素受体（AR）的非雄激素依赖性激活是潜在机制之一。最近的研究表明，通过 G 蛋白偶联受体 (GPCR) 发挥作用的激素会导致不依赖于雄激素的 AR 激活。我们最近报道，RGS2 是 RGS 超家族的成员，可通过前列腺癌细胞中的 GPCR 信号选择性抑制雄激素非依赖性 AR 激活。有趣的是，在已建立的前列腺癌细胞系中，RGS2 蛋白表达与雄激素非依赖性细胞增殖呈负相关。此外，与正常前列腺组织相比，人类前列腺癌标本的 RGS2 水平显着降低。因此，我们假设 RGS2 作为 AR 信号传导的新型调节剂，其抑制是前列腺肿瘤发生和进展的重要一步。具体目标： 1. 评估 RGS2 抑制在前列腺癌细胞中的生物学重要性。 2. 确定RGS2介导的雄激素非依赖性前列腺癌生长抑制的分子机制。 3. 阐明前列腺癌中RGS2抑制的机制。研究设计和方法：我们将首先检查改变 RGS2 表达对培养物和去势无胸腺裸鼠中前列腺癌细胞的雄激素非依赖性生长的影响。然后，我们将查明 RGS2 对其选择性抑制前列腺癌细胞中不依赖于雄激素的 AR 激活和细胞生长至关重要的氨基酸，并确定负责 RGS2 调节的 AR 结构域。最后，我们将结合甲基化特异性 PCR 和免疫组织化学分析来研究 RGS2 基因的甲基化是否与前列腺癌中 RGS2 抑制有关。然后将评估使用 RGS2 表达和/或 RGS2 甲基化状态作为前列腺癌诊断和预后的新标志物的可行性。除了甲基化之外，我们还将探讨基因改变或组蛋白修饰是否有助于前列腺癌中 RGS2 的抑制。有关 RGS2 在调节前列腺癌进展中的生物学重要性的信息与了解前列腺癌的生物学直接相关。完成拟议的研究不仅将为前列腺癌的进展提供潜在的诊断和预后标志物，而且还将有助于开发治疗前列腺癌的新药物。