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

// Christos Demosthenous 1, * , Jing Jing Han 1, * , Mary J. Stenson 1 , Matthew J. Maurer 1 , Linda E. Wellik 1 , Brian Link 2 , Kristen Hege 3 , Ahmet Dogan 4 , Eduardo Sotomayor 5 , Thomas Witzig 1 , Mamta Gupta 1 1 Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA 2 Department of Internal Medicine, University of Iowa College of Medicine, IA, USA 3 Celgene Corporation, San Francisco, CA, USA 4 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA 5 Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL, USA * These authors have contributed equally to this work Correspondence to: Mamta Gupta, e-mail: gupta.mamta@mayo.edu Keywords: translation initiation complex, eIF4E, lymphoma, dual mTOR inhibitors, CC214-1 Received: February 11, 2015      Accepted: February 12, 2015      Published: March 20, 2015 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.