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Translation initiation complex eIF4F is a therapeutic target for dual mTOR kinase inhibitors in non-Hodgkin lymphoma

Deregulated mRNA translation has been implicated in disease development and in part is controlled by a eukaryotic initiation complex eIF4F (composed of eIF4E, eIF4G and eIF4A). We demonstrate here that the cap bound fraction from lymphoma cells was enriched with eIF4G and eIF4E indicating that lymph...

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Autores principales: Demosthenous, Christos, Han, Jing Jing, Stenson, Mary J., Maurer, Matthew J., Wellik, Linda E., Link, Brian, Hege, Kristen, Dogan, Ahmet, Sotomayor, Eduardo, Witzig, Thomas, Gupta, Mamta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496233/
https://www.ncbi.nlm.nih.gov/pubmed/25839159
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author Demosthenous, Christos
Han, Jing Jing
Stenson, Mary J.
Maurer, Matthew J.
Wellik, Linda E.
Link, Brian
Hege, Kristen
Dogan, Ahmet
Sotomayor, Eduardo
Witzig, Thomas
Gupta, Mamta
author_facet Demosthenous, Christos
Han, Jing Jing
Stenson, Mary J.
Maurer, Matthew J.
Wellik, Linda E.
Link, Brian
Hege, Kristen
Dogan, Ahmet
Sotomayor, Eduardo
Witzig, Thomas
Gupta, Mamta
author_sort Demosthenous, Christos
collection PubMed
description Deregulated mRNA translation has been implicated in disease development and in part is controlled by a eukaryotic initiation complex eIF4F (composed of eIF4E, eIF4G and eIF4A). We demonstrate here that the cap bound fraction from lymphoma cells was enriched with eIF4G and eIF4E indicating that lymphoma cells exist in an activated translational state. Moreover, 77% (110/142) of diffuse large B cell lymphoma tumors expressed eIF4E and this was associated with an inferior event free survival. Over-expression of wild-type eIF4E (eIF4E(WT)) but not cap-mutant eIF4E (eIF4E(cap mutant)) increased the activation of the eIF4F complex. Treatment with the active-site dual mTOR inhibitor CC214-1 reduced the level of the eIF4F complex by decreasing the cap bound fraction of eIF4G and increasing the levels of 4E-BP1. CC214-1 inhibited both the cap dependent and global protein translation. CC214-1 inhibited c-Myc, and cyclin D3 translation by decreasing polysomal fractions from lymphoma cells. Inhibition of eIF4E with shRNA further decreased the CC214-1 induced inhibition of the eIF4F complex, c-Myc, cyclin D3 translation, and colony formation. These studies demonstrate that the eIF4F complex is deregulated in aggressive lymphoma and that dual mTOR therapy has therapeutic potential in these patients.
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spelling pubmed-44962332015-07-10 Translation initiation complex eIF4F is a therapeutic target for dual mTOR kinase inhibitors in non-Hodgkin lymphoma Demosthenous, Christos Han, Jing Jing Stenson, Mary J. Maurer, Matthew J. Wellik, Linda E. Link, Brian Hege, Kristen Dogan, Ahmet Sotomayor, Eduardo Witzig, Thomas Gupta, Mamta Oncotarget Research Paper Deregulated mRNA translation has been implicated in disease development and in part is controlled by a eukaryotic initiation complex eIF4F (composed of eIF4E, eIF4G and eIF4A). We demonstrate here that the cap bound fraction from lymphoma cells was enriched with eIF4G and eIF4E indicating that lymphoma cells exist in an activated translational state. Moreover, 77% (110/142) of diffuse large B cell lymphoma tumors expressed eIF4E and this was associated with an inferior event free survival. Over-expression of wild-type eIF4E (eIF4E(WT)) but not cap-mutant eIF4E (eIF4E(cap mutant)) increased the activation of the eIF4F complex. Treatment with the active-site dual mTOR inhibitor CC214-1 reduced the level of the eIF4F complex by decreasing the cap bound fraction of eIF4G and increasing the levels of 4E-BP1. CC214-1 inhibited both the cap dependent and global protein translation. CC214-1 inhibited c-Myc, and cyclin D3 translation by decreasing polysomal fractions from lymphoma cells. Inhibition of eIF4E with shRNA further decreased the CC214-1 induced inhibition of the eIF4F complex, c-Myc, cyclin D3 translation, and colony formation. These studies demonstrate that the eIF4F complex is deregulated in aggressive lymphoma and that dual mTOR therapy has therapeutic potential in these patients. Impact Journals LLC 2015-03-20 /pmc/articles/PMC4496233/ /pubmed/25839159 Text en Copyright: © 2015 Demosthenous 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
Demosthenous, Christos
Han, Jing Jing
Stenson, Mary J.
Maurer, Matthew J.
Wellik, Linda E.
Link, Brian
Hege, Kristen
Dogan, Ahmet
Sotomayor, Eduardo
Witzig, Thomas
Gupta, Mamta
Translation initiation complex eIF4F is a therapeutic target for dual mTOR kinase inhibitors in non-Hodgkin lymphoma
title Translation initiation complex eIF4F is a therapeutic target for dual mTOR kinase inhibitors in non-Hodgkin lymphoma
title_full Translation initiation complex eIF4F is a therapeutic target for dual mTOR kinase inhibitors in non-Hodgkin lymphoma
title_fullStr Translation initiation complex eIF4F is a therapeutic target for dual mTOR kinase inhibitors in non-Hodgkin lymphoma
title_full_unstemmed Translation initiation complex eIF4F is a therapeutic target for dual mTOR kinase inhibitors in non-Hodgkin lymphoma
title_short Translation initiation complex eIF4F is a therapeutic target for dual mTOR kinase inhibitors in non-Hodgkin lymphoma
title_sort translation initiation complex eif4f is a therapeutic target for dual mtor kinase inhibitors in non-hodgkin lymphoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496233/
https://www.ncbi.nlm.nih.gov/pubmed/25839159
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