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PEITC-mediated inhibition of mRNA translation is associated with both inhibition of mTORC1 and increased eIF2alpha phosphorylation in established cell lines and primary human leukemia cells

PEITC-mediated inhibition of mRNA translation is associated with both inhibition of mTORC1 and increased eIF2alpha phosphorylation in established cell lines and primary human leukemia cells
PEITC-mediated inhibition of mRNA translation is associated with both inhibition of mTORC1 and increased eIF2alpha phosphorylation in established cell lines and primary human leukemia cells
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 eIF2? phosphorylation. PEITC also increased formation of stress granules which are typically associated with eIF2? 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 eIF2? 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 eIF2? 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.
1949-2553
74807-74819
Yeomans, Alison
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Lemm, Elizabeth
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Wilmore, Sarah
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Cavell, Breeze
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Valle-Argos, Beatriz
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Krysov, Sergey
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Hidalgo, Marina
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Leonard, Elodie
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Willis, Anne E.
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Forconi, Francesco
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Stevenson, Freda
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Steele, Andrew
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Coldwell, Mark
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Packham, Graham
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Yeomans, Alison
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Lemm, Elizabeth
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Wilmore, Sarah
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Cavell, Breeze
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Valle-Argos, Beatriz
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Krysov, Sergey
3a78eac1-af40-4b37-8576-3462947649be
Hidalgo, Marina
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Leonard, Elodie
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Willis, Anne E.
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Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Stevenson, Freda
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Steele, Andrew
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Coldwell, Mark
a3432799-ed45-4948-9f7a-2a284d3ec65c
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394

Yeomans, Alison, Lemm, Elizabeth, Wilmore, Sarah, Cavell, Breeze, Valle-Argos, Beatriz, Krysov, Sergey, Hidalgo, Marina, Leonard, Elodie, Willis, Anne E., Forconi, Francesco, Stevenson, Freda, Steele, Andrew, Coldwell, Mark and Packham, Graham (2016) PEITC-mediated inhibition of mRNA translation is associated with both inhibition of mTORC1 and increased eIF2alpha phosphorylation in established cell lines and primary human leukemia cells Oncotarget, 7, (46), pp. 74807-74819. (doi:10.18632/oncotarget.11655). (PMID:27579538).

Record type: Article

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 eIF2? phosphorylation. PEITC also increased formation of stress granules which are typically associated with eIF2? 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 eIF2? 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 eIF2? 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.

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Accepted/In Press date: 27 July 2016
e-pub ahead of print date: 27 August 2016
Published date: 15 November 2016
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 400331
URI: https://eprints.soton.ac.uk/id/eprint/400331
ISSN: 1949-2553
PURE UUID: 11633217-11f8-4c3c-94e8-778da6a687ff
ORCID for Freda Stevenson: ORCID iD orcid.org/0000-0002-0933-5021
ORCID for Andrew Steele: ORCID iD orcid.org/0000-0003-0667-1596
ORCID for Mark Coldwell: ORCID iD orcid.org/0000-0002-6243-3886

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Date deposited: 14 Sep 2016 14:26
Last modified: 09 Jan 2018 17:52

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Contributors

Author: Alison Yeomans
Author: Elizabeth Lemm
Author: Sarah Wilmore
Author: Breeze Cavell
Author: Beatriz Valle-Argos
Author: Sergey Krysov
Author: Marina Hidalgo
Author: Elodie Leonard
Author: Anne E. Willis
Author: Freda Stevenson ORCID iD
Author: Andrew Steele ORCID iD
Author: Mark Coldwell ORCID iD
Author: Graham Packham

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