Role of Translational Control in Anti-Cancer Effects of PEITC

翻译控制在 PEITC 抗癌作用中的作用

• 批准号: 7530313
• 负责人: JING HU
• 金额: $ 17.04万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-14 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7530313
• 关键词: 5' Untranslated Regions; Accounting; Apoptosis; Apoptotic; Binding; Binding Proteins; Biological Markers; Cell Line; Cell model; Cells; Chemoprotective Agent; Colon Carcinoma; Colorectal Cancer; Complementary DNA; Data; Depth; Dietary Factors; Down-Regulation; Event; Gene Targeting; Genes; Goals; Growth; HCT116 Cells; HT29 Cells; In Vitro; Individual; Luciferases; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mediation; Molecular; Mus; Nude Mice; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Polyribosomes; Protein Biosynthesis; Protein Inhibition; Protein Overexpression; Protein Phosphatase 2A Regulatory Subunit PR53; Public Health; Rate; Regulation; Reporter; Resistance; Role; Signal Pathway; Signal Transduction; Structure; Subcutaneous Injections; Testing; Transcriptional Regulation; Translating; Translation Initiation; Translational Regulation; Translations; Xenograft Model; Xenograft procedure; cancer cell; cell growth; cruciferous vegetable; genetic manipulation; in vivo; inhibitor/antagonist; mRNA capping; prevent; protective effect; response; stem; tumor; tumor growth; tumor progression; tumor xenograft; vector

DESCRIPTION (provided by applicant): Dietary isothiocynates (ITC), including phenethylisothiocynate (PEITC), are major bioactive components of cruciferous vegetables. ITCs may greatly account for the cancer protective effect of cruciferous vegetables on various cancers such as colon cancer. We recently demonstrated that PEITC inhibits cap-dependent translation and inhibition of protein translation is critical for PEITC-induced apoptosis. Our long-term goal is to define the molecular mechanism of ITCs' chemoprotective actions. Our specific hypothesis is that the modulation of translational regulation contributes to PEITC-mediated chemoprotective effects. In this proposed study, we will focus on determining the potential upstream signaling and downstream target of PEITC-mediated translation inhibition. We also propose to determine whether the mechanistic information obtained from in vitro studies can be extended to in vivo. More specifically, we propose to: Aim 1. Examine the signaling pathways involved in the regulation of eIF4E availability for translation initiation. We will: (A) identify the signaling events responsible for PEITC-mediated inhibition of 4E-BP1 phosphorylation; and (B) determine whether PEITC inhibits eIF4E availability through targeting Mnk1/eIF4E phosphorylation pathway. Aim 2. Analyze PEITC-mediated changes in polyribosome profile. Polysome profile will be used to: A) Evaluate overall translation rate; B) Identify potential translational target mRNAs. Aim 3. Validate the role of eIF4E availability in PEITC-caused inhibition of tumor growth. To establish in vivo relevance, we will examine whether overexpression of eIF4E overcomes PEITC-mediated inhibition of xenograft growth. Tumors will be examined to determine the extent to which PEITC-induced inhibition of translation observed in cells (Aim 1 and 2) correlates with its effect in vivo. PUBLIC HEALTH RELEVANCE The proposed studies will provide in-depth mechanistic information regarding whether and how translational regulation plays a critical role in PEITC's chemoprotective effects. A better understanding of the linkage between translational regulation and PEITC's effects on tumor growth may ultimately result in discovery of effective biomarkers to assess dietary agent cancer protective effect.

描述（由申请人提供）： 膳食异硫氰酸盐（ITC），包括异硫氰酸苯乙酯（PEITC），是十字花科蔬菜的主要生物活性成分。 ITCs 可能在很大程度上解释了十字花科蔬菜对结肠癌等多种癌症的抗癌作用。我们最近证明 PEITC 抑制帽子依赖性翻译，并且蛋白质翻译的抑制对于 PEITC 诱导的细胞凋亡至关重要。我们的长期目标是明确 ITC 化学保护作用的分子机制。我们的具体假设是翻译调控的调节有助于 PEITC 介导的化学保护作用。在这项拟议的研究中，我们将重点确定 PEITC 介导的翻译抑制的潜在上游信号传导和下游靶标。我们还建议确定从体外研究获得的机制信息是否可以扩展到体内。更具体地说，我们建议： 目标 1. 检查参与调节 eIF4E 翻译起始可用性的信号通路。我们将： (A) 确定 PEITC 介导的 4E-BP1 磷酸化抑制作用的信号转导事件； (B) 确定 PEITC 是否通过靶向 Mnk1/eIF4E 磷酸化途径抑制 eIF4E 的可用性。目标 2. 分析 PEITC 介导的多核糖体谱变化。多核糖体概况将用于： A) 评估总体翻译率； B) 识别潜在的翻译靶标 mRNA。目标 3. 验证 eIF4E 在 PEITC 引起的肿瘤生长抑制中的作用。为了建立体内相关性，我们将检查 eIF4E 的过度表达是否克服了 PEITC 介导的异种移植物生长抑制。将检查肿瘤以确定细胞中观察到的 PEITC 诱导的翻译抑制与其体内效应的相关程度（目标 1 和 2）。公共健康相关性拟议的研究将提供有关翻译调控是否以及如何在 PEITC 化学保护作用中发挥关键作用的深入机制信息。更好地理解翻译调节和 PEITC 对肿瘤生长的影响之间的联系可能最终会发现有效的生物标志物来评估饮食剂的癌症保护作用。