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: 7715383
• 负责人: TIMOTHY TURNER
• 金额: $ 4.79万
• 依托单位: TUSKEGEE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-16 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7715383
• 关键词: African American; Americas; Androgens; Cell Adhesion; Cell Line; Cell Proliferation; Cells; Cetrorelix; Communities; Computer Retrieval of Information on Scientific Projects Database; Condition; Coupled; Data; Disease; Epidermal Growth Factor Receptor; Ethnic group; Funding; Gonadotropin Hormone Releasing Hormone; Gonadotropin-Releasing Hormone Analog; Grant; Human; In Vitro; Incidence; Institution; Invasive; Literature; Luteinizing Hormone-releasing Hormone Agonist; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Play; Prostate; Prostate carcinoma; Prostatic Neoplasms; Protein Kinase C; Rate; Receptor Signaling; Reporting; Research; Research Personnel; Resources; Role; Route; Signal Pathway; Signal Transduction; Source; Staging; Telomerase; United States; United States National Institutes of Health; attenuation; cancer cell; cell growth; in vivo; insight; male; men; mortality; prevent; response; 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 whether LHRH analogs alter prostate tumor telomerase expression in vitro.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 前列腺癌仍然是居住在美利坚合众国的男子中最常见的癌症。这种疾病对非裔美国人社区的影响甚至更具破坏性，非洲裔美国人男性的发病率和死亡率是美国所有种族中最高的。该项目的长期总体重点是了解促黄体生成素释放激素(LHRH)类似物西曲瑞克斯和表皮生长因子受体(EGFR)在前列腺癌细胞增殖和侵袭中的相互作用所涉及的复杂信号机制。我们相信，对这些细胞相互作用的深入了解将在旨在预防或限制前列腺癌向更具侵袭性的侵袭和转移阶段过渡的治疗方法的开发中发挥作用，并提供不同于针对早期致癌步骤的治疗方法的好处。 以前的文献报道支持LHRH类似物对雄激素非依赖的人前列腺细胞株产生抑制增殖作用的直接途径，DU-145结合我们的数据显示：1)DU-145在体内和体外的细胞生长和侵袭是通过EGFR介导的，2)EGFR信号的细胞反应受到蛋白激酶C(PKC)介导的负转调，这使我们假设LHRH激动剂的抗增殖作用是通过负衰减EGFR介导的，而EGFR被PKC磷酸化失活。我们建议在体外条件下利用强大的LHRH类似物Cetrorelx来阐明LHRH信号转导机制对人前列腺癌DU-145细胞的增殖和侵袭能力的影响。我们的具体目标是：1)确定LHRH类似物是否能在体外阻止前列腺癌的生长和/或侵袭和进展。2)确定LHRH类似物是否影响细胞黏附。3)确定LHRH类似物是否通过PKC介导的转调来实现其作用。4)体外检测LHRH类似物对前列腺癌端粒酶表达的影响。