Cargando…

Expression and activity of eIF6 trigger Malignant Pleural Mesothelioma growth in vivo

eIF6 is an antiassociation factor that regulates the availability of active 80S. Its activation is driven by the RACK1/PKCβ axis, in a mTORc1 independent manner. We previously described that eIF6 haploinsufficiency causes a striking survival in the Eμ-Myc mouse lymphoma model, with lifespans extende...

Descripción completa

Detalles Bibliográficos
Autores principales: Miluzio, Annarita, Oliveto, Stefania, Pesce, Elisa, Mutti, Luciano, Murer, Bruno, Grosso, Stefano, Ricciardi, Sara, Brina, Daniela, Biffo, Stefano
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741942/
https://www.ncbi.nlm.nih.gov/pubmed/26462016
_version_ 1782414105328484352
author Miluzio, Annarita
Oliveto, Stefania
Pesce, Elisa
Mutti, Luciano
Murer, Bruno
Grosso, Stefano
Ricciardi, Sara
Brina, Daniela
Biffo, Stefano
author_facet Miluzio, Annarita
Oliveto, Stefania
Pesce, Elisa
Mutti, Luciano
Murer, Bruno
Grosso, Stefano
Ricciardi, Sara
Brina, Daniela
Biffo, Stefano
author_sort Miluzio, Annarita
collection PubMed
description eIF6 is an antiassociation factor that regulates the availability of active 80S. Its activation is driven by the RACK1/PKCβ axis, in a mTORc1 independent manner. We previously described that eIF6 haploinsufficiency causes a striking survival in the Eμ-Myc mouse lymphoma model, with lifespans extended up to 18 months. Here we screen for eIF6 expression in human cancers. We show that Malignant Pleural Mesothelioma tumors (MPM) and a MPM cell line (REN cells) contain high levels of hyperphosphorylated eIF6. Enzastaurin is a PKC beta inhibitor used in clinical trials. We prove that Enzastaurin treatment decreases eIF6 phosphorylation rate, but not eIF6 protein stability. The growth of REN, in vivo, and metastasis are reduced by either Enzastaurin treatment or eIF6 shRNA. Molecular analysis reveals that eIF6 manipulation affects the metabolic status of malignant mesothelioma cells. Less glycolysis and less ATP content are evident in REN cells depleted for eIF6 or treated with Enzastaurin (Anti-Warburg effect). We propose that eIF6 is necessary for malignant mesothelioma growth, in vivo, and can be targeted by kinase inhibitors.
format Online
Article
Text
id pubmed-4741942
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-47419422016-03-17 Expression and activity of eIF6 trigger Malignant Pleural Mesothelioma growth in vivo Miluzio, Annarita Oliveto, Stefania Pesce, Elisa Mutti, Luciano Murer, Bruno Grosso, Stefano Ricciardi, Sara Brina, Daniela Biffo, Stefano Oncotarget Research Paper eIF6 is an antiassociation factor that regulates the availability of active 80S. Its activation is driven by the RACK1/PKCβ axis, in a mTORc1 independent manner. We previously described that eIF6 haploinsufficiency causes a striking survival in the Eμ-Myc mouse lymphoma model, with lifespans extended up to 18 months. Here we screen for eIF6 expression in human cancers. We show that Malignant Pleural Mesothelioma tumors (MPM) and a MPM cell line (REN cells) contain high levels of hyperphosphorylated eIF6. Enzastaurin is a PKC beta inhibitor used in clinical trials. We prove that Enzastaurin treatment decreases eIF6 phosphorylation rate, but not eIF6 protein stability. The growth of REN, in vivo, and metastasis are reduced by either Enzastaurin treatment or eIF6 shRNA. Molecular analysis reveals that eIF6 manipulation affects the metabolic status of malignant mesothelioma cells. Less glycolysis and less ATP content are evident in REN cells depleted for eIF6 or treated with Enzastaurin (Anti-Warburg effect). We propose that eIF6 is necessary for malignant mesothelioma growth, in vivo, and can be targeted by kinase inhibitors. Impact Journals LLC 2015-10-06 /pmc/articles/PMC4741942/ /pubmed/26462016 Text en Copyright: © 2015 Miluzio et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Miluzio, Annarita
Oliveto, Stefania
Pesce, Elisa
Mutti, Luciano
Murer, Bruno
Grosso, Stefano
Ricciardi, Sara
Brina, Daniela
Biffo, Stefano
Expression and activity of eIF6 trigger Malignant Pleural Mesothelioma growth in vivo
title Expression and activity of eIF6 trigger Malignant Pleural Mesothelioma growth in vivo
title_full Expression and activity of eIF6 trigger Malignant Pleural Mesothelioma growth in vivo
title_fullStr Expression and activity of eIF6 trigger Malignant Pleural Mesothelioma growth in vivo
title_full_unstemmed Expression and activity of eIF6 trigger Malignant Pleural Mesothelioma growth in vivo
title_short Expression and activity of eIF6 trigger Malignant Pleural Mesothelioma growth in vivo
title_sort expression and activity of eif6 trigger malignant pleural mesothelioma growth in vivo
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741942/
https://www.ncbi.nlm.nih.gov/pubmed/26462016
work_keys_str_mv AT miluzioannarita expressionandactivityofeif6triggermalignantpleuralmesotheliomagrowthinvivo
AT olivetostefania expressionandactivityofeif6triggermalignantpleuralmesotheliomagrowthinvivo
AT pesceelisa expressionandactivityofeif6triggermalignantpleuralmesotheliomagrowthinvivo
AT muttiluciano expressionandactivityofeif6triggermalignantpleuralmesotheliomagrowthinvivo
AT murerbruno expressionandactivityofeif6triggermalignantpleuralmesotheliomagrowthinvivo
AT grossostefano expressionandactivityofeif6triggermalignantpleuralmesotheliomagrowthinvivo
AT ricciardisara expressionandactivityofeif6triggermalignantpleuralmesotheliomagrowthinvivo
AT brinadaniela expressionandactivityofeif6triggermalignantpleuralmesotheliomagrowthinvivo
AT biffostefano expressionandactivityofeif6triggermalignantpleuralmesotheliomagrowthinvivo