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: 8212392
• 负责人: STEPHEN W BYERS
• 金额: $ 30.9万
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212392
• 关键词: AF2; Ablation; Adenomatous Polyposis Coli; Adverse effects; Affect; Agonist; Alleles; Animal Feed; Animal Model; Animals; Azoxymethane; Binding; Biological Assay; Calcium; Cancer Etiology; Cells; Cessation of life; Chemopreventive Agent; Cholecalciferol; Colon Carcinoma; Colorectal Cancer; Computer Simulation; Data; Development; Diet; Dietary intake; Epidemiologic Studies; Epithelium; Exhibits; Familial hypophosphatemic bone disease; Family; Genes; Goals; Growth; Health; 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; Regimen; Regulation; Reporter; Resistance; Role; Screening procedure; Series; Side; Signal Transduction; Specific qualifier value; Specificity; Structural Models; Sunlight; Testing; Therapeutic; Time; Transactivation; Transgenic Animals; Transgenic Mice; United States; Vitamin D; Vitamin D Analog; Vitamin D Response Element; Work; analog; beta catenin; biochemical model; cancer cell; dietary supplements; epidemiological model; 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，膳食摄入量或维生素 D 前体的紫外线激活与结肠癌的发病率之间存在关联。这种关系表明维生素 D 可能具有化学预防作用，动物研究已证实维生素 D 及其类似物对结肠癌的预防功效。然而，在许多情况下，人类癌细胞和肿瘤会对治疗产生抗药性。另一个主要问题是与维生素 D 的抗癌作用无关的副作用发生率很高。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) 相互作用介导的，但尚不清楚是否可以将它们分开。阐明维生素 D 发挥抗癌作用的精确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出对维生素治疗有抵抗力的患者有效的药物或饮食方案，和/或开发出副作用较少的治疗方法。初步数据表明，wnt/2-连环蛋白/TCF 致癌途径在结肠癌中几乎普遍激活，是维生素 D 及其类似物对结肠癌预防作用的关键中介。我们的数据表明，维生素 D 会抑制 2-连环蛋白信号传导，而 2-连环蛋白会激活 VDR。重要的是，我们发现某些 VDR 突变体和维生素 D 类似物可以与 2-连环蛋白相互作用，但不能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激活的概念。这种策略将提供在 VDR 激活的同时抑制 2-连环蛋白信号传导的额外好处。在目标一中，我们提出了一系列计算、结构和突变分析来识别 VDR 的结构特征，这些特征指定了它与 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库，以识别允许 2-连环蛋白但不允许其他共激活剂结合 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 类似物在防止 2-连环蛋白诱导的肿瘤形成中的作用。 APC1638 小鼠会出现自发性肠癌，我们最近培育出了 APC1638/VDR-/- 双基因动物。我们将使用 APC1638、APC1638/VDR-/-、VDR 突变体和氧化偶氮甲烷治疗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 的消除是否在肠道肿瘤发展中发挥作用。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腺瘤性结肠息肉病 (APC) 或 2-连环蛋白基因突变引起的。大量的流行病学和动物模型数据支持这样的假设：维生素 D 及其类似物（和阳光）是 CRC 的有效抑制剂，我们自己的工作表明，维生素 D 的某些类似物可以以 2-连环蛋白特异性方式抑制 CRC 的生长。我们现在提出一系列计算、生化和动物模型研究，以探索和利用维生素 D 途径可以在表达高水平活化 2-连环蛋白的结肠癌中优先激活的概念。

项目成果

Control of TCF-4 expression by VDR and vitamin D in the mouse mammary gland and colorectal cancer cell lines.

• DOI: 10.1371/journal.pone.0007872
• 发表时间: 2009-11-17
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Beildeck ME;Islam M;Shah S;Welsh J;Byers SW
• 通讯作者: Byers SW

Putative biomarkers and targets of estrogen receptor negative human breast cancer.

• DOI: 10.3390/ijms12074504
• 发表时间: 2011
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Sahab ZJ;Man YG;Byers SW;Sang QX
• 通讯作者: Sang QX

Alteration in protein expression in estrogen receptor alpha-negative human breast cancer tissues indicates a malignant and metastatic phenotype.

• DOI: 10.1007/s10585-010-9338-8
• 发表时间: 2010-10
• 期刊: CLINICAL & EXPERIMENTAL METASTASIS
• 影响因子: 4
• 作者: Sahab, Ziad J.;Man, Yan-Gao;Semaan, Suzan M.;Newcomer, Robert G.;Byers, Stephen W.;Sang, Qing-Xiang Amy
• 通讯作者: Sang, Qing-Xiang Amy

Tumor Suppressor RARRES1 Regulates DLG2, PP2A, VCP, EB1, and Ankrd26.

• DOI: 10.7150/jca.1.14
• 发表时间: 2010-06-02
• 期刊: Journal of Cancer
• 影响因子: 3.9
• 作者: Sahab ZJ;Hall MD;Zhang L;Cheema AK;Byers SW
• 通讯作者: Byers SW

Analysis of tubulin alpha-1A/1B C-terminal tail post-translational poly-glutamylation reveals novel modification sites.

• DOI: 10.1021/pr2011044
• 发表时间: 2012-03-02
• 期刊: JOURNAL OF PROTEOME RESEARCH
• 影响因子: 4.4
• 作者: Sahab, Ziad J.;Kirilyuk, Alexander;Zhang, Lihua;Khamis, Zahraa I.;Pompach, Petr;Sung, YouMe;Byers, Stephen W.
• 通讯作者: Byers, Stephen W.