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. ?

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 前列腺癌是美国诊断出的最常见癌症，大多数被诊断出的前列腺癌最终从雄激素依赖于雄激素独立的发展。然而，前列腺癌进展的确切分子机制尚不清楚，这是治疗前列腺癌的主要障碍。 该研究计划的长期目标是阐明前列腺癌偶联的内皮蛋白A受体（ETA R）信号在前列腺癌中的信号传导从雄激素依赖于雄激素独立于雄激素与分子机制的进展，并通过该机制来调节G蛋白信号2（RGS2）调节器2（RGS2）调节效果。 在我们的初步研究中，已选择LNCAP前列腺癌细胞系作为模型。它以低模型的方式以雄激素敏感的方式缓慢生长，但会积极生长，并在高音中失去了雄激素依赖性，从而模仿了人类前列腺癌的进展。我们发现，ETA R和RGS2表达的丧失与前列腺癌LNCAP细胞中雄激素反应的丧失有关，这两者都在人类前列腺肿瘤样品中得到了证实。我们的初步研究还表明，这两种改变可能会协同促进前列腺癌的进展。我们将通过以下特定目的进一步进行这些初步研究：目的1。确定ETA信号传导促进雄激素独立的前列腺癌细胞生长的分子机制。我们将研究ETA信号传导触发的多动性ERK活性是否负责雄激素独立的前列腺癌细胞增殖。我们还将通过小干扰RNA来静音雄激素受体，以确定雄激素受体在ETA信号触发的前列腺癌细胞增殖中的重要性。 目的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的LNCAP细胞中表达诱导型RGS2或使用siRNA在雄激素依赖性的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。目的3。确定RGS2失调的分子机制会导致前列腺癌的进展。我们将分析如何处理RGS2表达在雄激素受体Postitive LNCAP细胞以及其他雄激素受体阴性前列腺癌细胞系中负调节ETA信号传导和雄激素非依赖性恶性细胞生长。 这些研究的意义得到了强大的初步数据的支持，这是因为它们将提供有关分子机制的重要信息，从而增加ETA R和RGS2的丧失合作促进前列腺癌的进展。因此，与ETA R抑制剂结合使用，增加RGS2表达的药物可能对成功治疗晚期前列腺癌患者更有效。 ？