Role of Translational Control in Anti-Cancer Effects of PEITC

描述（由申请人提供）： 膳食异硫氰酸酯（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各种癌症如结肠癌的癌症保护作用。我们最近证明，PEITC抑制帽依赖性翻译和蛋白质翻译的抑制是PEITC诱导的细胞凋亡的关键。我们的长期目标是确定ITCs的化学保护作用的分子机制。我们的具体假设是，翻译调控的调制有助于PEITC介导的化学保护作用。在这项研究中，我们将重点关注PEITC介导的翻译抑制的潜在上游信号传导和下游靶点。我们还建议确定是否从体外研究中获得的机制信息可以扩展到体内。具体而言，我们建议：目标1。检查参与调节eIF 4 E翻译起始可用性的信号通路。我们将：（A）鉴定负责PEITC介导的4 E-BP 1磷酸化抑制的信号传导事件;和（B）确定PEITC是否通过靶向Mnk 1/eIF 4 E磷酸化途径抑制eIF 4 E可用性。目标2.分析PEITC介导的多聚核糖体谱的变化。多核糖体谱将用于：A）评价总体翻译速率; B）鉴定潜在的翻译靶mRNA。目标3。研究eIF 4 E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eIF 4 E的过表达是否克服了PEITC介导的异种移植物生长抑制。将检查肿瘤以确定在细胞中观察到的PEITC诱导的翻译抑制（目的1和2）与其体内作用相关的程度。公共卫生相关性拟议的研究将提供关于翻译调控是否以及如何在PEITC的化学保护作用中发挥关键作用的深入机制信息。更好地理解翻译调控和PEITC对肿瘤生长的影响之间的联系可能最终导致发现有效的生物标志物来评估膳食剂的癌症保护作用。

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.