IN VITRO ANALYSIS OF PROSTATE TUMOR INHIBITION BY LHRH ANALOGS

前列腺癌是男性最常见的癌症， 美国的 在诊断的时候。 其中一半以上 肿瘤已经侵入或转移。 前列腺的这个阶段 癌症进展不变地导致患者死亡，因为一旦 肿瘤会脱离其局部范围，对此没有治愈性疗法 疾病存在。 因此，最重要的是， 更好地理解肿瘤进展的生物学， 制定预防或限制前列腺肿瘤的治疗方法 转移到更具侵袭性的侵袭和转移阶段。 最近，促黄体生成激素释放激素（LHRH）的类似物已经被发现， 已经显示出对人具有抗增殖作用， 雄激素非依赖性前列腺细胞系DU-145。 在绑定其 受体，LHRH信号通路由磷脂酶C介导 (PLC)活动 PLC进而产生二酰基甘油（DAG）和 动员细胞内钙。 这些第二信使激活 蛋白质Lin7e C（PKQ; PKC直接磷酸化许多酶 负责激素的最终生物效应。 我们有 先前表明：1）DU-145细胞的生长和侵袭是 通过表皮生长因子受体（EGFR）介导，和2） EGFR信号传导的ceU应答受PKC介导的负性 互调 这些发现使我们假设， LXH的抗增殖作用C.激动剂通过 EGFR的负衰减，其被 磷酸化B，KC. 我们建议阐明LHRH信号 DU-145细胞增殖和侵袭的机制 使用有效的LHRH激动剂的体外条件。 我们的具体目标 本研究的目的是：1）确定LHRH类似物是否具有细胞毒性 涉及并能够抑制DU-145细胞侵袭性i. n Wtro。 （二） 确定LHRH类似物是否通过以下途径减弱EGFR信号传导 PKC介导的转调节。 3)确定LHRH I的能力 类似物以改变DU-145亚系的粘附条件。 的 这项研究的完成将最终提供我的答案 区分-LERH激动剂靶向哪种肿瘤细胞特性 以及实现这一点的线粒体机制。 因此，识别新的细胞内信号传导途径， 中断有望限制前列腺癌进展。

Prostate cancer is the most predominant cancer in men 'in the United States. At time of diagnosis. more than half I of these tumors have already invaded or metastasized. This stage of prostate cancer progression invariable leads to patient death since once the tumor escapes its local confines no curative therapies for this disease exist. Therefore, it is paramount that studies are directed at better understanding the biology of tumor progression and instituting therapies preventing or limiting the prostate tumors transition to more aggressive invasive and metastatic stages. Recently, analogs to luteinizing hormone releasing hormone (LHRH) have been shown to have i antiproliferative actions on the human, androgen-independent prostate cell line, DU-145. Upon binding its receptor, LHRH signaling pathways are mediated by phospholipase C (PLC) activity. PLC in turn generates diacylglycerol (DAG) and mobilizes intracellular calcium. These second messengers activate protein lin7e C (PKQ; PKC phosphorylates numerous enzymes directly responsible for the final biological effects of the hormone. We have previously shown that: 1) DU-145 cells growth and invasion are mediated through the epidermal growth factor receptor (EGFR), and 2) EGFR-signaled ceU responses are subject to PKC-mediated negative transmodulation. These findings have lead us to hypothesize that the antiproliferative effects of LXH C. agonists arc mediated through negative attenuation of the EGFR which is inactivated by phosphorylation b, KC. We propose to elucidate LHRH signafing mechanism for cell proliferation and invasiveness in DU-145 ce& under in vitro conditions utilizing potent LHRH agonists. Our specific aims for this study are: 1) To ascertain if LHRH analogues are cytotoxic to and capable of inhibiting DU-145 cell invasiveness i . n Wtro. 2) Determine whether LHRH analogues attenuate EGFR signaling via PKC-mediated transmodulation. 3) Determine the ability of LHRH I analogs to alter adhesive condition s of DU-145 sublines. The completion of this research will ultimately provide I answers to distinguish- which tumor cell property is targeted by LERH agonists and the mitracellular mechanism by which this is accomplished. Consequently identifying novel intracellular signaling pathways whose disruption hold promise for restricting prostate cancer progression.