权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

RECEPTOR SIGNALING, PHYTIC ACID AND PROSTATE CANCER

受体信号传导、植酸和前列腺癌

基本信息

批准号：
6626716
负责人：
Rajesh Agarwal
金额：
$ 18.79万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-01-10 至 2004-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6626716
关键词：
apoptosis athymic mouse cell growth regulation epidermal growth factor growth factor receptors inositol phosphates molecular oncology nutrition aspect of cancer nutrition related tag phosphatidylinositol 3 kinase prostate neoplasms protein tyrosine kinase receptor mediated endocytosis

项目摘要

Overall goal of the grant is to conduct in depth studies to identify and develop molecular-mechanism based intervention approach for human prostate cancer (PCA) by a dietary agent phytic acid. Aberrant expression of epidermal growth factor receptor family members (erbB) is shown with high frequency in prostatic intraepithelial neoplasia and invasive human PCA suggesting their role in the causation of this disease. In addition to receptor activation, ligand binding also results in a rapid disappearance of receptor from cell surface via endocytosis by promoting receptor clustering into clathrin- coated pits on membrane followed by receptor internalization. A main structural component of coated pits is clathrin lattice anchored to membrane by associated protein adaptors (Aps). AP2 is the most ubiquitous of associated proteins that specifically interact with erbB receptors. In addition to receptor, the other step is fluid-phase endocytosis mediated via P13K-AKT-Rab5 pathway. Based on high association between receptor endocytosis and mitogenic and anti-apoptotic responses, we hypothesize that impairment of both receptor-mediated and fluid-phase endocytosis, and the mitogenic and anti-apoptotic signaling associated with them is an obligatory step in the inhibition/retardation of PCA growth. In support of this hypothesis, we observed that endocytosis is operational in human PCA cells, and that a dietary agent phytic acid impairs endocytosis and mitogenic responses associated with it. Together, efforts are directed in this grant to impair receptor endocytosis signaling leading to inhibition of both mitogenic and anti-apoptotic responses as a novel and innovative strategy for the intervention of PCA by phytic acid. Using PCA cells, we will assess the inhibitory effect of phytic acid on 1) ligand-induced erbB receptor endocytosis signaling, and define the involvement of AP2 and P13K-AKT-Rab5 pathways in this process; and 2) MAPK-mediated growth and P13K-AKT-BAD- mediated anti-apoptotic pathways in response to impairment of receptor endocytosis signaling. Next, we will assess the biological significance of phytic acid on growth inhibition and/or apoptotic death of human PCA cells using both in vitro and in vivo systems, and define the involvement of molecular events identified above. The outcome of these studies will build a base for future long term studies to a) further define the role of receptor endocytosis signaling and associated events in human PCA as molecular target(s) for intervention, and b) evaluate the effect of phytic acid against PCA in investigative clinical trials with correlative laboratory studies.

该资助的总体目标是进行深入研究，以确定和开发基于分子机制的饮食剂植酸干预人类前列腺癌（PCA）的方法。表皮生长因子受体家族成员 (erbB) 的异常表达在前列腺上皮内瘤变和侵袭性人类 PCA 中频繁出现，表明它们在导致该疾病的过程中发挥着重要作用。除了受体激活之外，配体结合还通过促进受体聚集到膜上网格蛋白包被的凹坑中，然后受体内化，从而通过内吞作用导致受体从细胞表面快速消失。包被凹坑的主要结构成分是网格蛋白晶格，通过相关的蛋白质接头（Aps）锚定在膜上。 AP2 是最普遍存在的与 erbB 受体特异性相互作用的相关蛋白。除了受体之外，另一个步骤是通过 P13K-AKT-Rab5 途径介导的液相内吞作用。基于受体内吞作用与促有丝分裂和抗凋亡反应之间的高度关联，我们假设受体介导的内吞作用和液相内吞作用以及与之相关的促有丝分裂和抗凋亡信号传导的损害是抑制/延缓 PCA 生长的必要步骤。为了支持这一假设，我们观察到内吞作用在人 PCA 细胞中发挥作用，并且饮食剂植酸会损害与其相关的内吞作用和有丝分裂反应。此次资助的共同目标是损害受体内吞信号传导，从而抑制促有丝分裂和抗凋亡反应，作为植酸干预 PCA 的新颖和创新策略。使用 PCA 细胞，我们将评估植酸对 1) 配体诱导的 erbB 受体内吞信号传导的抑制作用，并确定 AP2 和 P13K-AKT-Rab5 通路在此过程中的参与； 2) MAPK 介导的生长和 P13K-AKT-BAD 介导的抗凋亡途径，以响应受体内吞信号传导的受损。接下来，我们将使用体外和体内系统评估植酸对人 PCA 细胞生长抑制和/或凋亡死亡的生物学意义，并定义上述分子事件的参与。这些研究的结果将为未来的长期研究奠定基础：a) 进一步明确受体内吞信号传导和人类 PCA 中相关事件作为干预分子靶标的作用；b) 在研究性临床试验和相关实验室研究中评估植酸对 PCA 的作用。