Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/38529
Title: PEITC-mediated inhibition of mRNA translation is associated with both inhibition of mTORC1 and increased eIF2α phosphorylation in established cell lines and primary human leukemia cells.
Authors: Yeomans, A.
Lemm, E.
Wilmore, S.
Cavell, B. E.
Valle-Argos, B.
Krysov, S.
Sanchez Hidalgo, M.
Leonard, E.
Willis, Anne E.
Forconi, F.
Stevenson, F. K.
Steele, A. J.
Coldwell, M. J..
Packham, G.
First Published: 27-Aug-2016
Publisher: Impact Journals
Citation: Oncotarget, 2016
Abstract: Increased mRNA translation drives carcinogenesis and is an attractive target for the development of new anti-cancer drugs. In this work, we investigated effects of phenethylisothiocyanate (PEITC), a phytochemical with chemopreventive and anti-cancer activity, on mRNA translation. PEITC rapidly inhibited global mRNA translation in human breast cancer-derived MCF7 cells and mouse embryonic fibroblasts (MEFs). In addition to the known inhibitory effects of PEITC on mTORC1 activity, we demonstrate that PEITC increased eIF2α phosphorylation. PEITC also increased formation of stress granules which are typically associated with eIF2α phosphorylation and accumulation of translationally stalled mRNAs. Analysis of genetically modified MEFs demonstrated that optimal inhibition of global mRNA translation by PEITC was dependent on eIF2α phosphorylation, but not mTORC1 inhibition. We extended this study into primary leukemic B cells derived from patients with chronic lymphocytic leukaemia (CLL). CLL cells were stimulated in vitro with anti-IgM to mimic binding of antigen, a major driver of this leukemia. In CLL cells, PEITC increased eIF2α phosphorylation, inhibited anti-IgM-induced mTORC1 activation and decreased both basal and anti-IgM-induced global mRNA translation. PEITC also inhibited transcription and translation of MYC mRNA and accumulation of the MYC oncoprotein, in anti-IgM-stimulated cells. Moreover, treatment of CLL cells with PEITC and the BTK kinase inhibitor ibrutinib decreased anti-IgM-induced translation and induced cell death to a greater extent than either agent alone. Therefore, PEITC can inhibit both global and mRNA specific translation (including MYC) via effects on multiple regulatory pathways. Inhibition of mRNA translation may contribute to the chemopreventive and anti-cancer effects of PEITC.
DOI Link: 10.18632/oncotarget.11655
eISSN: 1949-2553
Links: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=11655
http://hdl.handle.net/2381/38529
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Creative Commons Attribution 3.0 License
Appears in Collections:Published Articles, Dept. of Molecular and Cell Biology

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