Genistein-mediated Regulation of Prostate Cancer Cell Motility

金雀异黄素介导的前列腺癌细胞运动性调节

• 批准号: 8113270
• 负责人: Raymond C. Bergan
• 金额: $ 30.45万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-23 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113270
• 关键词: ACVR1 gene; Actins; Address; Affect; Animals; Behavior; Binding; Biological Process; Cancer Etiology; Cause of Death; Cell Adhesion; Cell Adhesion Molecules; Cells; Cessation of life; Chemicals; Chemopreventive Agent; Clinical; Clinical Trials Design; Complex; Consumption; Dependence; Development; Effectiveness; Endoglin; Epidemiology; Focal Adhesions; Genes; Genistein; Health; Heat Shock Protein 27; Human; In Vitro; Incidence; Integrin Binding; Integrins; Investigation; Link; MMP2 gene; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic Prostate Cancer; Modeling; Molecular; Molecular Target; Mus; Neoplasm Metastasis; Pathway interactions; Phase; Phase II Clinical Trials; Pre-Clinical Model; Prevention strategy; Prostate; Proteins; Public Health; Regulation; Regulatory Pathway; Role; Signal Pathway; Signal Transduction; Signaling Protein; Tissue Banking; Tissue Banks; Tissues; Work; base; cancer cell; carcinogenesis; cell motility; design; human tissue; in vivo; male; man; men; mutant; phase 2 study; pre-clinical; prevent; protein expression; receptor; soy; tumor progression

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.

描述（由申请人提供）： 前列腺癌（PCA）死亡是由前列腺中PCA细胞转移性传播引起的。染料木黄酮的饮食消费与转移性PCA的发病率较低有关。在临床前模型中，染料木黄酮以与饮食消费有关的浓度抑制PCA细胞运动和转移。在一项前瞻性设计的临床试验中，染料木黄酮对人的前列腺细胞施加抗糖效率。我们假设Genastein治疗可以调节调节PCA细胞运动性的人的信号通路。我们已经阐明了人类PCA细胞调节运动性的两种信号通路：（1）染料木黄酮抑制的热休克蛋白27（HSP27）促动力途径。 （2）染料木黄酮激活的内尾抗动力途径。在动物中，染料木黄酮抑制人类PCA转移。在PCA男性的第1阶段和第2阶段试验中，染料木黄酮的耐受性良好，抑制前列腺细胞脱离，并选择性地调节调节PCA细胞运动的基因。我们提出的三个目标旨在提高我们对PCA细胞如何调节运动性，染料木黄酮如何调节这些调节途径以及染料木黄酮对人的影响的理解。 AIM 1阐明了内聚肽（TGF2超家族辅助受体）调节PCA细胞运动的机制，并确定它们在介导Gegistein的功效中的作用。研究将确定哪种TGF2 II型受体亚型对于内形信号传导是必需的。他们还将通过结合整合蛋白粘附分子来确定内og介介导细胞运动。将评估染料木黄酮对每种机制的依赖性。 AIM 2确定HSP27是否通过修饰肌动蛋白功能来抑制染料木黄酮疗效。 Hsp27-肌动蛋白相互作用在调节细胞粘附和浸润以及染料木黄酮疗效中的作用将得到确定。随着HSP27在人为PCA进展过程中的调节，鼠研究将评估HSP27是否调节PCA转移性行为，以及其表达如何影响染料木黄酮抗转移性疗效。 AIM 3评估染料木黄酮是否改变了调节前列腺细胞运动性的人的分子途径。使用我们2阶段试验中的排列前列腺组织，研究将确定染料木黄酮是否在人分子水平上施加与治疗相关的抗动力效应。对人体组织进行的研究将部分通过在目标1和2中进行的研究来决定。前列腺癌通过在整个体内移动而导致死亡，从而形成转移。公共卫生相关性古碱性是一种大豆的化学物质，可抑制动物的转移。我们已经表明，在人类中，染料木黄酮似乎阻止了前列腺细胞移动。该提议试图找出染料木黄酮在人中的工作方式。为了能够使用染料木黄酮有效抑制人类的前列腺癌转移，因此需要此信息。