COBRE; CREIGHTON UNIV; P10; PROSTATE CANCER: THE ROLE OF G-PROTEIN ALPHA12

科布雷；

• 批准号: 7610589
• 负责人: YAPING TU
• 金额: $ 32.92万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610589
• 关键词: Androgen Receptor; Androgens; Biological; Cancer Cell Growth; Cancer Patient; Cell Proliferation; Cells; Centers of Research Excellence; Computer Retrieval of Information on Scientific Projects Database; Coupled; Data; Dependence; Development; Endothelin; Endothelin A Receptor; Funding; G12 Protein; GTP-Binding Proteins; Goals; Grant; Growth; Institution; LNCaP; Malignant - descriptor; Malignant neoplasm of prostate; Medicine; Modeling; Molecular; Nude Mice; PC3 cell line; Prostate; Prostatic Neoplasms; Receptor Signaling; Research; Research Personnel; Resources; Role; Sampling; Signal Transduction; Small Interfering RNA; Source; United States National Institutes of Health; androgen independent prostate cancer; cancer cell; cancer diagnosis; cell growth; human RGS2 protein; inhibitor/antagonist; programs; tumor progression

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Prostate cancer is the most common cancer diagnosed in the USA and the majority of prostate cancers diagnosed eventually progress from being androgen-dependent to androgen-independent. However, the precise molecular mechanisms underlying prostate cancer progression are unknown, which presents a major hurdle for the treatment of prostate cancer. The long-term goals of this research program are to elucidate the precise role of G-protein coupled endothelin A receptor (ETA R) signaling in prostate cancer progression from being androgen-dependent to androgen-independent and the molecular mechanisms whereby Regulator of G-protein Signaling 2 (RGS2) modulates the ETAR signaling in this progression. The LNCaP prostate cancer cell line has been chosen as a model in our preliminary studies. It grows slowly in an androgen-sensitive manner at low-passage but grows aggressively and loses androgen-dependence in high-passage, mimicking the progression of human prostate cancers. We found that increased ETA R and loss of RGS2 expression are associated with the loss of androgen-responsiveness in prostate cancer LNCaP cells, which both have been confirmed in human prostate tumor samples. Our preliminary studies also suggested that these two alterations may cooperatively promote prostate cancer progression. We will pursue these preliminary studies further through the following specific aims: Aim 1. To determine molecular mechanisms whereby ETA R signaling promotes androgen-independent prostate cancer cell growth. We will investigate whether the hyperactive ERK activity triggered by ETA R signaling is responsible for androgen-independent prostate cancer cell proliferation. We will also silence androgen receptor by small interfering RNA to determine the importance of androgen receptor in ETA R signaling-triggered proliferation of prostate cancer cells. Aim 2. To study the biological importance of RGS2 in prostate cancer progression. We will investigate whether RGS2 negatively modulates prostate cancer by either expressing inducible RGS2 in androgen-independent LNCaP cells or using siRNA to silence RGS2 in androgen-dependent LNCaP cells. We will also study the effects of manipulating RGS2 on the malignant growth of prostate cancer cells in culture and in athymic nude mice. Aim 3. To determine the molecular mechanisms whereby dysregulation of RGS2 contributes prostate cancer progression. We will analyze how manipulating RGS2 expression negatively regulates the ETA R signaling and androgen-independent malignant cell growth in androgen receptor postitive LNCaP cells and in other androgen receptor negative prostate cancer cell lines. The significance of these studies, which are supported by strong preliminary data, resides in the fact that they will provide important information on the molecular mechanisms whereby increased ETA R and loss of RGS2 cooperatively promote prostate cancer progression. Therefore, development of medicines that increase the RGS2 expression, in combination with ETA R inhibitors, may prove more effective for the successful treatment of advanced prostate cancer patients. ?

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 前列腺癌是在美国诊断出的最常见的癌症，大多数诊断出的前列腺癌最终从雄激素依赖性进展为雄激素非依赖性。然而，前列腺癌进展的确切分子机制尚不清楚，这给前列腺癌的治疗带来了主要障碍。 该研究计划的长期目标是阐明 G 蛋白偶联内皮素 A 受体 (ETA R) 信号在前列腺癌从雄激素依赖性到雄激素非依赖性进展中的精确作用，以及 G 蛋白偶联内皮素 A 受体 (ETA R) 信号调节的分子机制。蛋白信号转导 2 (RGS2) 在此过程中调节 ETAR 信号转导。 LNCaP 前列腺癌细胞系已被选为我们初步研究的模型。它在低传代时以雄激素敏感的方式缓慢生长，但在高传代时快速生长并失去雄激素依赖性，模仿人类前列腺癌的进展。我们发现，ETA R 的增加和 RGS2 表达的丧失与前列腺癌 LNCaP 细胞雄激素反应性的丧失有关，这两者都已在人类前列腺肿瘤样本中得到证实。我们的初步研究还表明，这两种改变可能共同促进前列腺癌的进展。我们将通过以下具体目标进一步开展这些初步研究： 目标 1. 确定 ETA R 信号传导促进雄激素非依赖性前列腺癌细胞生长的分子机制。我们将研究 ETA R 信号传导引发的过度活跃的 ERK 活性是否与雄激素非依赖性前列腺癌细胞增殖有关。我们还将通过小干扰RNA沉默雄激素受体，以确定雄激素受体在ETA R信号触发的前列腺癌细胞增殖中的重要性。 目标 2. 研究 RGS2 在前列腺癌进展中的生物学重要性。 我们将研究 RGS2 是否通过在雄激素非依赖性 LNCaP 细胞中表达诱导型 RGS2 或使用 siRNA 在雄激素依赖性 LNCaP 细胞中沉默 RGS2 来负调节前列腺癌。我们还将研究操纵 RGS2 对培养物和无胸腺裸鼠中前列腺癌细胞恶性生长的影响。目标 3. 确定 RGS2 失调导致前列腺癌进展的分子机制。我们将分析操纵 RGS2 表达如何负向调节雄激素受体阳性 LNCaP 细胞和其他雄激素受体阴性前列腺癌细胞系中的 ETA R 信号转导和雄激素非依赖性恶性细胞生长。 这些研究得到了强有力的初步数据的支持，其重要性在于，它们将提供有关 ETA R 增加和 RGS2 缺失协同促进前列腺癌进展的分子机制的重要信息。因此，开发增加RGS2表达的药物，与ETA R抑制剂联合使用，可能对成功治疗晚期前列腺癌患者更有效。 ？