Mechanisms of Wnt/beta-catenin inhibition by resveratrol and its derivatives

白藜芦醇及其衍生物抑制Wnt/β-catenin的机制

基本信息

批准号：
8191422
负责人：
CHUNMING LIU
金额：
$ 16.15万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-10 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8191422
关键词：
APC gene Accounting Adenomatous Polyposis Coli Biological Factors Biometry Blueberries CTNNB1 gene Cancer Center Cancer Etiology Cancer Model Cell Proliferation Cell model Cessation of life Chemicals Chemoprevention Chemopreventive Agent Clinical Clinical Research Colitis Colon Colon Carcinoma Colorectal Cancer Dimethylhydrazines Exhibits Future Genes Goals Grapes Growth Hand In Vitro Inflammation Interdisciplinary Study Lead Malignant Neoplasms Modeling Modification Molecular Molecular Target Mus Mutation New Agents Nude Mice Pathology Pathway interactions Pharmaceutical Preparations Physicians Plants Proteomics Publications Research Resveratrol Signal Transduction Skin Staging Stilbenes Testing Toxic effect United States Universities Work Xenograft procedure adenoma analog base beta catenin bioactive food component cancer cell cancer chemoprevention cancer prevention cancer therapy colon carcinogenesis colorectal cancer prevention design in vivo inhibitor/antagonist insight mortality mouse model novel phytoalexin phytoalexins prevent red wine response trans-resveratrol tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): This is a revised application in response to PA-10-088, "Exploratory Cancer Prevention Studies Involving Molecular Targets for Bioactive Food Components (R21)". In this project, we will characterize a novel molecular target of resveratrol for colorectal cancer prevention. Colorectal cancer is the second leading cause of cancer-related mortality in the United States and accounts for more than 56,000 deaths per year. Colorectal cancer is initiated by mutations of adenomatous polyposis coli (APC) and 2-catenin genes, which result in abnormal activation of Wnt signaling. Inhibition Wnt signaling is essential for colorectal cancer chemoprevention. Resveratrol is found in the skin of red grape and also present in the red wine. Resveratrol and many of its analogs have anti-cancer activity. We found several resveratrol analogs, including pterostilbene found in blueberry, can strongly inhibit Wnt signaling, while cis-resveratrol cannot. We have designed and synthesized a panel of novel resveratrol analogs and have identified several novel inhibitors for Wnt/2-catenin signaling. Our central hypothesis is that resveratrol and its analogs inhibit Wnt signaling, thus prevent of 2-catenin-induced cancers, particularly colorectal cancers. To further understand the molecular mechanisms of resveratrol in Wnt/2-catenin inhibition and to develop better inhibitors for chemoprevention, we will pursue the following two specific aims: 1) to delineate the mechanisms of how resveratrol inhibits Wnt signaling using cell models; and 2) to investigate how resveratrol and its analogs inhibits Wnt signaling using a novel inflammation-related mouse colon cancer model. PUBLIC HEALTH RELEVANCE: Colorectal cancer is the second leading cause of cancer death in the United States. This project is to explore a novel mechanism of cancer prevention by resveratrol, a product from red grapes. We found that resveratrol blocks Wnt signaling, a key pathway in colon cancer formation. The studies in this project will provide a better understanding of resveratrol function in cancer prevention and will lead to better chemoprevention agents in the future.

描述（由申请人提供）：这是对PA-10-088的修订应用，“涉及生物活性食品成分分子靶标（R21）的探索性癌症预防研究”。在这个项目中，我们将表征用于预防大肠癌的白藜芦醇的新型分子靶标。大肠癌是美国与癌症相关死亡率的第二大原因，每年造成56,000多人死亡。结直肠癌是由腺瘤性息肉病（APC）和2-catenin基因的突变引发的，这导致Wnt信号的异常激活。抑制Wnt信号对于结直肠癌化学预防至关重要。白藜芦醇在红葡萄的皮肤中发现，也存在于红酒中。白藜芦醇及其许多类似物具有抗癌活性。我们发现几种白藜芦醇类似物，包括在蓝莓中发现的翼龙，可以强烈抑制Wnt信号传导，而顺式白藜芦醇则不能。我们设计并合成了一系列新型白藜芦醇类似物，并确定了Wnt/2-catenin信号传导的几种新型抑制剂。我们的中心假设是白藜芦醇及其类似物抑制了Wnt信号传导，从而阻止了2-Catenin诱导的癌症，尤其是结直肠癌。为了进一步了解白藜芦醇在Wnt/2-catenin抑制中的分子机制，并为化学预防开发更好的抑制剂，我们将追求以下两个具体目的：1）描述白藜芦醇如何使用细胞模型抑制Wnt信号的机制； 2）研究白藜芦醇及其类似物如何使用新型炎症相关的小鼠结肠癌模型抑制Wnt信号传导。公共卫生相关性：大肠癌是美国癌症死亡的第二大原因。该项目是为了探索红葡萄产物的白藜芦醇预防癌症预防的新机制。我们发现白藜芦醇阻止了Wnt信号传导，这是结肠癌形成的关键途径。该项目中的研究将更好地了解预防癌症中的白藜芦醇功能，并将在未来提供更好的化学预防剂。