Genistein-mediated Regulation of Prostate Cancer Cell Motility

描述（由申请人提供）： 前列腺癌（PCa）死亡是由前列腺的PCa细胞转移性扩散引起的。膳食摄入染料木黄酮与转移性前列腺癌的发生率较低相关。在临床前模型中，染料木黄酮在与饮食消耗相关的浓度下抑制PCa细胞运动和转移。在一项前瞻性设计的临床试验中，染料木黄酮对人前列腺细胞产生抗运动作用。我们假设染料木黄酮治疗性调节人前列腺癌细胞运动的信号通路。我们已经阐明了两条人前列腺癌细胞调节运动的信号通路：（1）热休克蛋白27（HSP 27）促运动通路被染料木黄酮抑制。(2)由染料木黄酮激活的内皮糖蛋白抗运动通路。在动物中，染料木黄酮抑制人PCa转移。在前列腺癌患者的1期和2期试验中，染料木黄酮耐受性良好，抑制前列腺细胞脱落，并选择性调节调节前列腺癌细胞运动的基因。我们提出了三个目的，旨在增加我们的理解如何PCa细胞调节运动，如何genistein调节这些调节途径，和genistein在man. Aim 1阐明endoglin（TGF-2超家族辅助受体）调节PCa细胞运动的机制，并确定其在介导genistein的疗效的作用。研究将确定哪些TGF 2 II型受体亚型是内皮糖蛋白信号传导所必需的。他们还将确定内皮糖蛋白是否通过与整合素粘附分子结合来介导细胞运动。染料木黄酮对这些机制的依赖性将进行评估。目的2确定热休克蛋白27是否通过修饰肌动蛋白功能抑制染料木黄酮的药效。热休克蛋白27-肌动蛋白相互作用的作用，在调节细胞粘附和侵袭，和染料木黄酮的疗效，将被确定。由于HSP 27在人类前列腺癌进展过程中上调，因此鼠研究将评估HSP 27是否调节前列腺癌转移行为，以及其表达如何影响染料木黄酮抗转移功效。目的3评估染料木黄酮是否改变调节前列腺细胞运动的分子通路。使用来自我们的2期试验的储存的前列腺组织，研究将确定染料木黄酮是否在分子水平上对人体产生治疗相关的抗运动作用。对人体组织进行的研究将部分取决于目标1和2中进行的研究。前列腺癌通过在全身移动而导致死亡，从而形成转移。金雀异黄素是大豆中的一种化学物质，可以抑制动物的转移。我们已经证明，在人类中，染料木黄酮似乎阻止前列腺细胞移动。这项建议旨在找出染料木黄酮是如何在人体内工作的，这些信息是必要的，以便能够使用染料木黄酮有效地抑制前列腺癌转移的人。

DESCRIPTION (provided by applicant): Death from prostate cancer (PCa) is caused by the metastatic dissemination of PCa cells from the prostate gland. Dietary consumption of genistein is associated with a lower incidence metastatic PCa. In preclinical models genistein inhibits PCa cell motility and metastasis at concentrations linked to dietary consumption. In a prospectively designed clinical trial, genistein exerts antimotility efficacy on prostate cells in man. We hypothesize that genistein therapeutically modulates signaling pathways in man that regulate PCa cell motility. We have elucidated two signaling pathways by which human PCa cells regulate motility: (1) the heat shock protein 27 (HSP27) pro-motility pathway-inhibited by genistein. (2) the endoglin anti-motility pathway-activated by genistein. In animals, genistein inhibits human PCa metastasis. In phase 1 and phase 2 trials in men with PCa, genistein is well tolerated, inhibits prostate cell detachment, and selectively modulates genes which regulate PCa cell motility. We propose three Aims designed to increase our understanding of how PCa cells regulate motility, of how genistein modulates those regulatory pathways, and of genistein's effect in man. Aim 1 Elucidate the mechanisms by which endoglin (a TGF2 superfamily accessory receptor) regulates PCa cell motility, and determine their role in mediating genistein's efficacy. Studies will identify which TGF2 type II receptor subtype is necessary for endoglin signaling. They will also determine whether endoglin mediates cell motility by binding to integrin adhesion molecules. Genistein's dependence upon each of these mechanisms will be evaluated. Aim 2 Determine whether HSP27 inhibits genistein efficacy by modifying actin function. The role of HSP27-actin interaction in regulating cell adhesion and invasion, and genistein efficacy, will be determined. As HSP27 is up regulated during PCa progression in man, murine studies will assess whether HSP27 regulates PCa metastatic behavior, and how its expression affects genistein antimetastatic efficacy. Aim 3 Assess if genistein alters molecular pathways in man which regulate prostate cell motility. Using banked prostate tissue from our phase 2 trial, investigations will determine whether genistein exerts therapeutically relevant anti-motility effects at the molecular level in man. Studies performed upon human tissue will be dictated, in part, by investigations performed in Aims 1 and 2. Prostate cancer causes death by moving throughout the body, thereby forming metastasis. PUBLIC HEALTH RELEVANCE Genistein is a chemical in soy that inhibits metastasis in animals. We have shown that in man, genistein appears to stop prostate cells from moving. This proposal seeks to find out how genistein is working in man. This information is necessary in order be able to use genistein to effectively inhibit prostate cancer metastasis in man.