Beta-catenin-specific regulation of the vitamin D pathway in colon cancer

结肠癌中维生素 D 通路的 β-连环蛋白特异性调节

• 批准号: 7464481
• 负责人: STEPHEN W BYERS
• 金额: $ 31.85万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-04 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7464481
• 关键词: AF2; Ablation; Adenomatous Polyposis Coli; Adverse effects; Affect; Agonist; Alleles; Animal Cancer Model; Animal Feed; Animal Model; Animals; Azoxymethane; Binding; Biochemical; Biological Assay; Calcium; Cancer Etiology; Cells; Cessation of life; Chemopreventive Agent; Cholecalciferol; Colon Carcinoma; Colorectal Cancer; Data; Development; Dietary intake; Epidemiologic Studies; Epithelium; Exhibits; Familial hypophosphatemic bone disease; Family; Genes; Goals; Growth; Human; Hyperplasia; Incidence; Inherited; Intestinal Cancer; Intestinal Neoplasms; Intestines; Knockout Mice; Lead; Libraries; Ligands; Malignant Neoplasms; Mediating; Mus; Mutation; Neoplasms; Nuclear; Nuclear Receptors; Oncogenic; Pathway interactions; Patients; Phenotype; Play; Point Mutation; Predisposition; Preventive; Principal Investigator; Property; Public Health; Regulation; Reporter; Resistance; Role; Screening procedure; Series; Side; Signal Transduction; Specific qualifier value; Specificity; Sunlight; Testing; Therapeutic; Time; Transactivation; Transgenic Animals; Transgenic Mice; Treatment Protocols; United States; Vitamin D; Vitamin D Analog; Vitamin D Response Element; Work; ZK 191784; analog; beta catenin; cancer cell; concept; dietary supplements; feeding; in vivo; inhibitor/antagonist; malignant colon tumor; model development; mutant; programs; promoter; simulation; small molecule libraries; therapy development; thyroid hormone receptor associated protein 220; tumor; tumorigenesis; virtual; vitamin therapy; yeast two hybrid system

DESCRIPTION (provided by applicant): Epidemiological studies show a relationship between the dietary intake or UV-activation of pre-vitamin D and the incidence of colon cancers. This relationship indicates that vitamin D may have a chemopreventive action and animal studies have confirmed the preventive efficacy of vitamin D and its analogues in colon cancer. However in many instances human cancer cells and tumors become resistant to treatment. Another major concern is the high incidence of side effects unrelated to the anti cancer actions of vitamin D. Even though both the cancer- and non-cancer-related actions of vitamin D are mediated via interaction with its nuclear receptor (VDR) it is not clear if they can be separated. Studies that elucidate the precise mechanism(s) whereby vitamin D exerts its anti-cancer effects are of great significance. A detailed understanding of these pathways may lead to the development of agents or dietary regimens that are effective in patients that are resistant to vitamin therapy and/or to the development of treatments with fewer side effects. Preliminary data demonstrates that the wnt/2- catenin/TCF oncogenic pathway, almost universally activated in colon cancer, is a key intermediary in the preventive action of vitamin D and its analogues in colon cancer. Our data shows that vitamin D represses 2-catenin signaling and that 2-catenin activates VDR. Importantly, we find that certain VDR mutants and vitamin D analogues allow interaction with 2-catenin but not other co-activators. This proposal seeks to explore and exploit the concept that the vitamin D pathway can be selectively activated in intestinal cancer cells expressing high levels of activated 2-catenin. Such a strategy would offer the additional benefit of repressing 2-catenin signaling at the same time as VDR is activated. In aim one we propose a series of computational, structural, and mutational analyses to identify structural features of the VDR, which specify its interaction with 2-catenin. In aim two we will screen virtual and real libraries to identify ligands which allow 2-catenin but not other co-activators to bind the VDR. Our goal is to develop vitamin D analogues that can activate VDR only in situations, such as colon cancer, in which 2-catenin is elevated. In aim three we will use transgenic animals to investigate the role of VDR, VDR mutants and 2- catenin specific vitamin D analogues in protection from 2-catenin induced neoplasia. The APC1638 mouse develops spontaneous intestinal cancers and we recently generated APC1638/VDR-/- bigenic animals. We will use APC1638 ,APC1638/VDR-/-, VDR-mutant and azoxymethane treated animals to investigate the ability of vitamin D analogues to support VDR/2-catenin interactions and whether ablation of VDR plays any role in intestinal tumor development. PUBLIC HEALTH RELEVANCE: Colorectal cancer is the second leading cause of cancer-related death in the United States. The development of virtually all colorectal cancer results from mutation in adenomatous polyposis coli (APC) or 2-catenin genes. A wealth of epidemiological and animal model data supports the hypothesis that vitamin D and its analogues (and sunlight) are potent inhibitors of CRC and our own work shows that certain analogues of vitamin D can inhibit the growth of CRC in a 2-catenin-specific manner. We now propose a series of computational, biochemical and animal model studies to explore and exploit the concept that the vitamin D pathway can be preferentially activated in colon cancers which express high levels of activated 2-catenin.

描述（由申请人提供）： 流行病学研究表明，饮食摄入或前维生素D的紫外线激活与结肠癌的发病率之间存在关系。这种关系表明，维生素D可能具有化学预防作用，动物研究已经证实了维生素D及其类似物对结肠癌的预防作用。然而，在许多情况下，人类癌细胞和肿瘤对治疗产生抗性。另一个主要问题是与维生素D抗癌作用无关的副作用的高发生率。尽管维生素D的癌症和非癌症相关作用都是通过与其核受体（VDR）的相互作用介导的，但尚不清楚它们是否可以分开。阐明维生素D发挥其抗癌作用的确切机制的研究具有重要意义。对这些途径的详细了解可能会导致开发对维生素治疗耐药的患者有效的药物或饮食方案和/或开发副作用较少的治疗方法。初步数据表明，wnt/2- catenin/TCF致癌途径，几乎普遍激活结肠癌，是一个关键的中介在预防行动的维生素D及其类似物在结肠癌。我们的数据表明，维生素D抑制2-catenin信号，2-catenin激活VDR。重要的是，我们发现某些VDR突变体和维生素D类似物允许与2-连环蛋白相互作用，但不允许与其他共激活剂相互作用。该提案旨在探索和利用维生素D途径可以在表达高水平活化2-连环蛋白的肠癌细胞中选择性活化的概念。这种策略将提供在VDR被激活的同时抑制2-连环蛋白信号传导的额外益处。在目标一，我们提出了一系列的计算，结构和突变分析，以确定VDR的结构特征，指定其与2-连环蛋白的相互作用。在目标二中，我们将筛选虚拟和真实的文库以鉴定允许2-连环蛋白而不是其他共激活剂结合VDR的配体。我们的目标是开发维生素D类似物，仅在结肠癌等2-连环蛋白升高的情况下才能激活VDR。在目标三中，我们将使用转基因动物来研究VDR、VDR突变体和2-连环蛋白特异性维生素D类似物在保护免受2-连环蛋白诱导的瘤形成中的作用。APC 1638小鼠发生自发性肠癌，我们最近产生了APC 1638/VDR-/-双基因动物。我们将使用APC 1638、APC 1638/VDR-/-、VDR突变体和氧化偶氮甲烷处理的动物来研究维生素D类似物支持VDR/2-连环蛋白相互作用的能力以及VDR的消融是否在肠肿瘤发展中起任何作用。公共卫生相关性：结直肠癌是美国癌症相关死亡的第二大原因。几乎所有结直肠癌的发生都是由于腺瘤性结肠息肉病（APC）或2-连环蛋白基因突变所致。大量的流行病学和动物模型数据支持维生素D及其类似物（和阳光）是CRC的有效抑制剂的假设，我们自己的工作表明，某些维生素D类似物可以以2-连环蛋白特异性方式抑制CRC的生长。我们现在提出了一系列的计算，生物化学和动物模型研究，探索和利用的概念，维生素D途径可以优先激活结肠癌表达高水平的活化2-连环蛋白。