Role of Translational Control in Anti-Cancer Effects of PEITC

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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.