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: 7561452
• 负责人: TIMOTHY TURNER
• 金额: $ 8.99万
• 依托单位: TUSKEGEE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7561452
• 关键词: 1,2-diacylglycerol; Androgens; Biology; Cell Adhesion; Cell Line; Cells; Computer Retrieval of Information on Scientific Projects Database; Condition; Data; Diagnosis; Diglycerides; Disruption; Epidermal Growth Factor Receptor; Funding; Gonadotropin Hormone Releasing Hormone; Gonadotropin-Releasing Hormone Analog; Grant; Growth; Hormones; Human; In Vitro; Inhibition of Cell Proliferation; Institution; Invaded; Lead; Luteinizing Hormone-releasing Hormone Agonist; Malignant neoplasm of prostate; Mammary Neoplasms; Mediating; Modeling; Molecular Profiling; Neoplasm Metastasis; Pathway interactions; Phospholipase C; Phosphorylation; Pituitary Gland; Prostate; Prostatic Neoplasms; Protein Kinase C; Receptor Signaling; Regulation; Research; Research Personnel; Resources; Screening for Prostate Cancer; Signal Pathway; Signal Transduction; Source; Telomerase; Time; United States National Institutes of Health; analog; attenuation; cell growth; novel therapeutics; prevent; response; therapeutic target; tumor; tumor growth; 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. At the time of diagnosis, more than half of prostate tumors have invaded and metastasized. Early detection of prostate cancer is not a fail-safe cure since the tumors can quickly attain hormone-independence. Thus, it is imperative that we understand the biology of tumor growth regulation to define new therapeutic targets. Luteinizing hormone releasing hormone (LHRH) and its analogs directly inhibit growth of human, androgen independent prostate cell lines, including DU-145. The mechanism by which these analogs exert their antiproliferative effects is unknown. We propose that LHRH analogs limit the pro-growth signaling through the epidermal growth factor receptor (EGFR). Previously we have shown that: 1) DU-145 cells growth and invasion are mediated through the EGFR, and 2) EGFR-signaled cell responses are subject to PKC-mediated negative transmodulation by direct phosphorylatation of the EGFR. Although the data on LHRH signaling in prostate cells is still uncertain, LHRH agonists stimulate phospholipase-C (PLC) activity in mammary tumors in a similar manner as LHRH does in the pituitary gland. Our model has PLC activity generating diacylglycerol (DAG) and mobilizing intracellular Ca2+ to activate protein kinase C PKC). These findings lead 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 propose to elucidate LHRH signaling mechanism for inhibition of cell proliferation and invasion in DU-145 cells under in vitro conditions utilizing potent LHRH analogs. Our specific aims for this study are to determine whether LHRH analogs: 1) Prevent prostate tumor growth and/or invasion in vitro. 2) Influence cell adhesion profile. 3) Achieve their effects via PKC-mediated transmodulation. 4) Alter the telomerase expression profile. The successful completeion of this project will elucidate the intracellular mechanism by which LHRH analogs exert their antiproliferative effect. This will identify intracellular pathways whose disruption hold promise for restricting prostate cancer progression.

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。 在诊断时，超过一半的前列腺肿瘤已经浸润和转移。 前列腺癌的早期检测并不是万无一失的治疗方法，因为肿瘤可以很快达到激素非依赖性。 因此，我们必须了解肿瘤生长调节的生物学，以确定新的治疗靶点。 促黄体激素释放激素（LHRH）及其类似物直接抑制人雄激素非依赖性前列腺细胞系（包括DU-145）的生长。这些类似物发挥其抗增殖作用的机制尚不清楚。 我们提出LHRH类似物通过表皮生长因子受体（EGFR）限制促生长信号传导。 之前我们已经证明：1）DU-145细胞的生长和侵袭是通过EGFR介导的，2）EGFR信号传导的细胞应答通过EGFR的直接磷酸化受到PKC介导的负性反式调节。 虽然前列腺细胞中LHRH信号的数据仍不确定，但LHRH激动剂刺激乳腺肿瘤中磷脂酶C（PLC）活性的方式与LHRH在脑垂体中的方式相似。 我们的模型具有PLC活性，产生二酰基甘油（DAG）并动员细胞内Ca 2+以激活蛋白激酶C（PKC）。 这些发现使我们推测LHRH激动剂的抗增殖作用是通过EGFR的负衰减介导的，EGFR通过PKC的磷酸化而失活。 我们建议阐明LHRH信号转导机制抑制细胞增殖和侵袭DU-145细胞在体外条件下，利用有效的LHRH类似物。 本研究的具体目的是确定LHRH类似物是否：1）在体外预防前列腺肿瘤生长和/或侵袭。 2)影响细胞粘附特性。 3)通过PKC介导的转调节实现其作用。 4)改变端粒酶表达谱。 该项目的成功完成将有助于阐明LHRH类似物发挥抗增殖作用的细胞内机制。 这将确定细胞内通路，其中断有望限制前列腺癌的进展。