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

Christos Demosthenous; Brian Link; Jing Jing Han; Mary J Stenson; Matthew J Maurer; Linda E Wellik; Kristen Hege; Ahmet Dogan; Eduardo Sotomayor; Thomas Witzig; Mamta Gupta

doi:10.18632/oncotarget.3378

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

Journal article

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Peer reviewed

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

Christos Demosthenous, Brian Link, Jing Jing Han, Mary J Stenson, Matthew J Maurer, Linda E Wellik, Kristen Hege, Ahmet Dogan, Eduardo Sotomayor, Thomas Witzig, …

Oncotarget, Vol.6(11), pp.9488-9501

04/20/2015

DOI: 10.18632/oncotarget.3378

PMCID: PMC4496233

PMID: 25839159

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Abstract

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.

RNA, Small Interfering - genetics

Protein Biosynthesis

Humans

Neoplasm Proteins - physiology

Gene Expression Regulation, Neoplastic

Neoplasm Proteins - antagonists & inhibitors

Molecular Targeted Therapy

Phosphoproteins - metabolism

RNA Caps - metabolism

RNA, Neoplasm - metabolism

TOR Serine-Threonine Kinases - antagonists & inhibitors

Proto-Oncogene Proteins c-myc - biosynthesis

Eukaryotic Initiation Factor-4G - analysis

Protein Processing, Post-Translational - drug effects

RNA Interference

Cyclin D3 - genetics

HEK293 Cells

Phosphorylation - drug effects

Eukaryotic Initiation Factor-4F - antagonists & inhibitors

Tumor Stem Cell Assay

Lymphoma, Large B-Cell, Diffuse - drug therapy

Eukaryotic Initiation Factor-4F - physiology

Neoplasm Invasiveness

Lymphoma, Large B-Cell, Diffuse - enzymology

Eukaryotic Initiation Factor-4E - analysis

Imidazoles - pharmacology

Cyclin D3 - biosynthesis

Cell Line, Tumor

RNA, Neoplasm - genetics

Neoplasm Proteins - analysis

Protein Kinase Inhibitors - pharmacology

Proto-Oncogene Proteins c-myc - genetics

Adaptor Proteins, Signal Transducing - metabolism

Pyrazines - pharmacology

Lymphoma, Large B-Cell, Diffuse - genetics

Details

Title: Subtitle: Translation initiation complex eIF4F is a therapeutic target for dual mTOR kinase inhibitors in non-Hodgkin lymphoma
Creators: Christos Demosthenous - Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
Brian Link - Department of Internal Medicine, University of Iowa College of Medicine, IA, USA
Jing Jing Han - Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
Mary J Stenson - Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
Matthew J Maurer - Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
Linda E Wellik - Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
Kristen Hege - Celgene Corporation, San Francisco, CA, USA
Ahmet Dogan - Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Eduardo Sotomayor - Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
Thomas Witzig - Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
Mamta Gupta - Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
Resource Type: Journal article
Publication Details: Oncotarget, Vol.6(11), pp.9488-9501
DOI: 10.18632/oncotarget.3378
PMID: 25839159
PMCID: PMC4496233
NLM abbreviation: Oncotarget
ISSN: 1949-2553
eISSN: 1949-2553
Grant note: P50 CA097274 / NCI NIH HHS
Language: English
Date published: 04/20/2015
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094361802771

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