IN VITRO ANALYSIS OF PROSTATE TUMOR INHIBITION BY LHRH ANALOGS

前列腺癌是世界上最常见的男性癌症。 美国。在诊断时。其中一半以上是我 肿瘤已经侵袭或转移。前列腺癌的这一阶段 癌症进展不变会导致患者死亡，因为一旦 肿瘤逃脱了它的局部限制，没有治愈的方法 疾病是存在的。因此，最重要的是，研究的方向是 更好地了解肿瘤进展的生物学和 制定预防或限制前列腺癌的治疗方法 过渡到更具侵袭性的侵袭性和转移性阶段。 最近，促黄体生成素释放激素(LHRH)的类似物已经 已经被证明对人类有抗增殖作用， 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 动员细胞内的钙离子。这第二个信使激活 蛋白lin7E C(PKQ；PKC)直接磷酸化多种酶 对荷尔蒙的最终生物效应负责。我们有 以往研究表明：1)DU-145细胞的生长和侵袭 通过表皮生长因子受体(EGFR)介导，和2) EGFR信号的CEU反应容易受到PKC介导的阴性反应的影响 转调。这些发现使我们假设 LXH-C激动剂的抗增殖作用是通过 使EGFR失活的负衰减率 磷酸化b，Kc。我们建议澄清LHRH信令 DU-145Ce&Under细胞增殖和侵袭机制的研究 在体外条件下使用有效的LHRH激动剂。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 对DU-145细胞侵袭力有抑制作用。N Wtro.2) 确定LHRH类似物是否通过 PKC介导的转调。3)确定LHRH I的能力 类似物改变DU-145亚系S的黏附条件。这个 这项研究的完成将最终为以下问题提供答案 区分-LERH激动剂针对的肿瘤细胞特性 以及实现这一点的有丝分裂细胞机制。 因此确定了新的细胞内信号通路，其 阻断有望限制前列腺癌的进展。

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.