IDENTIFYING SIGNALING PATHWAYS PROSTATE TUMOR INHIBITION BY LHRH ANALOGS

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。 在诊断时，超过一半的前列腺癌已经侵袭和转移。早期发现前列腺癌并不是万无一失的治疗方法，因为肿瘤可以很快实现激素依赖。因此，我们必须了解肿瘤生长调节的生物学原理，以确定新的治疗靶点。促黄体生成素释放激素(LHRH)及其类似物直接抑制人雄激素非依赖性前列腺细胞系的生长，包括DU-145。这些类似物发挥抗增殖作用的机制尚不清楚。我们认为LHRH类似物通过表皮生长因子受体(EGFR)限制促生长信号。以前我们已经证明：1)DU-145细胞的生长和侵袭是通过EGFR介导的，2)EGFR信号的细胞反应是通过EGFR的直接磷酸化而受到PKC介导的负向转调的。虽然有关前列腺细胞中LHRH信号的数据仍不确定，但LHRH激动剂刺激乳腺肿瘤中的磷脂酶C(PLC)活性的方式与LHRH在脑垂体中的作用类似。我们的模型具有PLC生成二酰甘油(DAG)和动员细胞内钙离子激活蛋白激酶C(PKC)的活性。这些发现使我们假设，LHRH激动剂的抗增殖作用是通过负衰减EGFR介导的，而EGFR通过PKC的磷酸化而失活。我们建议利用有效的LHRH类似物在体外条件下阐明LHRH抑制DU-145细胞增殖和侵袭的信号机制。我们这项研究的具体目的是确定LHRH类似物是否：1)在体外防止前列腺癌的生长和/或侵袭。2)影响细胞黏附特性。3)通过PKC介导的转调来实现它们的作用。4)改变端粒酶表达谱。该项目的成功完成将阐明LHRH类似物发挥抗增殖作用的细胞内机制。这将确定其破坏的细胞内通路有望限制前列腺癌的进展。

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.