RECEPTOR SIGNALING, PHYTIC ACID AND PROSTATE CANCER

受体信号传导、植酸和前列腺癌

• 批准号: 6418131
• 负责人: Rajesh Agarwal
• 金额: $ 17.71万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-10 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6418131
• 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

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.

这笔赠款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植酸饮食制剂对人类前列腺癌(PCA)的干预方法。表皮生长因子受体家族成员(ErbB)在前列腺上皮内瘤变和侵袭性前列腺癌中的异常表达频率较高，提示其在前列腺癌的发病机制中起重要作用。除了受体的激活，配体结合还通过内吞作用促进受体聚集到细胞膜上被笼罩的凹坑中，从而导致受体内化，从而导致受体从细胞表面迅速消失。包被坑的一个主要结构成分是通过相关蛋白适配器(APS)锚定在膜上的网状蛋白晶格。AP2是最普遍存在的与erbB受体特异性相互作用的相关蛋白。除受体外，另一步是通过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反应和抗凋亡反应之间的高度相关性，我们假设，受体介导的和液相内吞作用的损害，以及与之相关的促有丝分裂和抗凋亡信号是抑制/抑制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前列腺癌细胞中是可操作的，并且膳食制剂植酸损害了内吞作用和与之相关的有丝分裂反应。总之，这项赠款旨在削弱受体内吞作用信号，导致抑制有丝分裂和抗凋亡反应，作为植酸干预PCA的一种新颖和创新的策略。利用PCa细胞，我们将评估植酸对1)配体诱导的erbB受体内吞信号的抑制作用，并确定AP2和P13K-AKT-Rab5通路在这一过程中的参与；以及2)MAPK介导的生长和P13K-AKT-BAD介导的抗凋亡通路对受体内吞信号的损伤。接下来，我们将使用体外和体内系统评估植酸对人前列腺癌细胞生长抑制和/或凋亡死亡的生物学意义，并确定上述分子事件的参与。这些研究结果将为未来的长期研究奠定基础，以a)进一步明确受体内吞信号及其相关事件在人前列腺癌中的作用，作为干预的分子靶点(S)，以及b)结合相关的实验室研究在调查性临床试验中评估植酸对前列腺癌的影响。