Genistein-mediated Regulation of Prostate Cancer Cell Motility

描述(由申请人提供)： 前列腺癌死亡(PCA)是由前列腺癌细胞的转移扩散引起的。饮食中食用染料木素与较低的转移性前列腺癌发生率相关。在临床前模型中，金雀异黄素抑制前列腺癌细胞的运动和转移，其浓度与饮食摄入量有关。在一项前瞻性设计的临床试验中，金雀异黄素对人体前列腺细胞具有抗运动性作用。我们假设金雀异黄素在治疗上调节人体内调节前列腺癌细胞运动的信号通路。我们阐明了人前列腺癌细胞调节运动的两条信号通路：(1)热休克蛋白27(HSP27)前运动通路-被金雀异黄素抑制。(2)金雀异黄素激活的endoglin抗运动通路。在动物实验中，金雀异黄素抑制人前列腺癌的转移。在前列腺癌男性患者的1期和2期试验中，金雀异黄素耐受性良好，可以抑制前列腺细胞分离，并选择性地调节调节前列腺癌细胞运动的基因。我们提出了三个目标，旨在增加我们对前列腺癌细胞如何调节运动性、金雀异黄素如何调节这些调节途径以及金雀异黄素在人类中的作用的理解。目的1阐明血管内皮生长因子2超家族附属受体endoglin调节前列腺癌细胞运动的机制，并确定其在染料木素效应中的作用。研究将确定哪些TGF2 II型受体亚型是endoglin信号传递所必需的。他们还将确定endoglin是否通过与整合素黏附分子结合来调节细胞运动。金雀异黄素对上述每一种机制的依赖性将被评估。目的2确定热休克蛋白27是否通过改变肌动蛋白功能而抑制染料木素的作用。HSP27-肌动蛋白相互作用在调节细胞黏附和侵袭中的作用，以及金雀异黄素的疗效，将被确定。由于HSP27在人类PCa进展过程中上调，小鼠研究将评估HSP27是否调节PCa转移行为，以及其表达如何影响Genistein的抗转移疗效。目的3评估金雀异黄素是否改变了调节前列腺细胞运动的分子通路。使用我们第二阶段试验中储存的前列腺组织，研究将确定金雀异黄素是否在分子水平上对人类发挥治疗相关的抗运动作用。对人体组织进行的研究将在一定程度上取决于AIMS 1和AIMS 2中进行的研究。前列腺癌通过在全身转移而导致死亡，从而形成转移。与公共健康相关的染料木素是大豆中的一种化学物质，可以抑制动物体内的转移。我们已经证明，在人类中，金雀异黄素似乎可以阻止前列腺细胞移动。这项提议试图找出染料木素是如何在人类体内发挥作用的。为了能够使用金雀异黄素有效地抑制前列腺癌的转移，这些信息是必要的。

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.