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

Authors: Demosthenous, C.; Han, J. J.; Stenson, M. J.; Maurer, M. J.; Wellik, L. E.; Link, B.; Hege, K.; Dogan, A.; Sotomayor, E.; Witzig, T.; Gupta, M.
Article Title: Translation initiation complex eIF4F is a therapeutic target for dual mTOR kinase inhibitors in non-Hodgkin lymphoma
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. Overexpression of wild-type eIF4E (eIF4EWT) but not cap-mutant eIF4E (eIF4Ecap 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.
Keywords: adult; controlled study; event free survival; human tissue; unclassified drug; major clinical study; cell growth; nonhodgkin lymphoma; myc protein; protein mcl 1; lymphoma; initiation factor 4e; initiation factor 4e binding protein 1; rna translation; large cell lymphoma; mammalian target of rapamycin inhibitor; short hairpin rna; protein modification; cyclin d3; colony formation; translation regulation; initiation factor 4g; initiation factor 4f; human; male; female; article; &eif4e; cc214-1; dual mtor inhibitors; translation initiation complex; cc 214 1; cap dependent protein translation; mantle cell lymphoma cell
Journal Title: Oncotarget
Volume: 6
Issue: 11
ISSN: 1949-2553
Publisher: Impact Journals  
Date Published: 2015-04-20
Start Page: 9488
End Page: 9501
Language: English
PROVIDER: scopus
PUBMED: 25839159
PMCID: PMC4496233
DOI: 10.18632/oncotarget.3378
Notes: Export Date: 3 June 2015 -- Source: Scopus
Citation Impact
MSK Authors
  1. Ahmet Dogan
    305 Dogan