IDENTIFYING SIGNALING PATHWAYS PROSTATE TUMOR INHIBITION BY LHRH ANALOGS

确定 LHRH 类似物抑制前列腺肿瘤的信号通路

• 批准号: 7959272
• 负责人: TIMOTHY TURNER
• 金额: $ 4.6万
• 依托单位: TUSKEGEE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-18 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959272
• 关键词: African American; Americas; Androgens; Biomedical Research; Cell Adhesion; Cell Line; Cell Proliferation; Cells; Cetrorelix; Communities; Computer Retrieval of Information on Scientific Projects Database; Coupled; Data; Disease; Epidermal Growth Factor Receptor; Ethnic group; Funding; Gonadotropin Hormone Releasing Hormone; Gonadotropin-Releasing Hormone Analog; Grant; Human; In Vitro; Incidence; Institution; Literature; Luteinizing Hormone-releasing Hormone Agonist; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; PC3 cell line; Play; Prostate; Prostate carcinoma; Prostatic Neoplasms; Protein Kinase C; Receptor Signaling; Reporting; Research; Research Personnel; Resources; Role; Route; Signal Pathway; Signal Transduction; Source; Staging; United States; United States National Institutes of Health; attenuation; cancer cell; cell growth; cytotoxicity; in vivo; insight; male; men; mortality; prevent; response; synthetic peptide; therapy development; tumor growth

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 continues to be the most prevalent cancer in men residing in the United States of America. The effects of this disease on the African American community has been even more devastating, with African American males having the highest incidence and mortality rate of any ethnic group in America. The long-term, overall thrust of this project was to understand the intricate signaling mechanisms involved in the crosstalk between the luteinizing hormone releasing hormone (LHRH) analog, Cetrorelix and the epidermal growth factor receptor (EGFR) in prostate cancer cell proliferation and invasion. We believed gaining insight into these cellular interactions would play a role in the development of therapies directed at preventing or limiting prostate tumor transition to the more aggressive invasive and metastatic stages, as well as offer different benefits than those therapies targeting early carcinogenic steps. Previous reports in the literature supporting a direct route for LHRH analogs to produce antiproliferative actions on the human, androgen-independent prostate cell line, DU-145 coupled with our data showing that: 1) DU-145 in vivo and in vitro cell growth and invasion are mediated through EGFR and 2) EGFR-signaled cell responses are subject to protein kinase C (PKC)-mediated negative transmodulation led us to hypothesize that the antiproliferative effects of LHRH agonists are mediated through negative attenuation of the EGFR which is inactivated by phosphorylation by PKC. We proposed to elucidate LHRH signaling mechanism for cell proliferation and invasiveness in human prostate carcinoma-derived DU-145 cells under in vitro conditions utilizing the potent LHRH analog, Cetrorelix. Our specific aims were to: 1) Determine whether LHRH analogs prevent prostate tumor growth and/or invasion and progression in vitro. 2) Determine whether LHRH analogs can influence cell adhesion. 3) Determine whether LHRH analogs achieve their effects via PKC-mediated transmodulation. 4) Determine the cytotoxicity of synthetic peptides on prostate cancer cell lines.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 前列腺癌仍然是居住在美利坚合众国的男性中最常见的癌症。这种疾病对非裔美国人社区的影响甚至更具破坏性，非裔美国人男性的发病率和死亡率是美国任何族裔群体中最高的。该项目的长期总体目标是了解前列腺癌细胞增殖和侵袭中促黄体生成素释放激素（LHRH）类似物西曲瑞克和表皮生长因子受体（EGFR）之间串扰所涉及的复杂信号传导机制。 我们相信，深入了解这些细胞相互作用将在开发旨在预防或限制前列腺肿瘤转变为更具侵袭性的侵袭性和转移性阶段的疗法中发挥作用，并提供与针对早期致癌步骤的疗法不同的益处。 文献中的先前报告支持LHRH类似物对人类雄激素非依赖性前列腺细胞系DU-145产生抗增殖作用的直接途径，我们的数据显示：1）DU-145体内和体外细胞生长和侵袭通过EGFR介导，2）EGFR信号传导的细胞应答受蛋白激酶C（PKC）的影响。介导的负性转调节使我们假设LHRH激动剂的抗增殖作用是通过EGFR的负性衰减介导的，EGFR被PKC磷酸化灭活。我们提出了阐明LHRH信号转导机制的细胞增殖和侵袭性的人前列腺癌细胞衍生的DU-145细胞在体外条件下，利用有效的LHRH类似物，西曲瑞克。 我们的具体目标是：1）确定LHRH类似物是否在体外预防前列腺肿瘤生长和/或侵袭和进展。2)确定LHRH类似物是否可以影响细胞粘附。3)确定LHRH类似物是否通过PKC介导的反式调节实现其作用。4)测定合成肽对前列腺癌细胞系的细胞毒性。