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. 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.
authors.affiliation: Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Christos
authors.initials: C
authors.lastname: Demosthenous
authors.affiliation: Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jing Jing
authors.initials: JJ
authors.lastname: Han
authors.affiliation: Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Stenson
authors.affiliation: Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Maurer
authors.affiliation: Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Linda E
authors.initials: LE
authors.lastname: Wellik
authors.affiliation: Department of Internal Medicine, University of Iowa College of Medicine, IA, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Link
authors.affiliation: Celgene Corporation, San Francisco, CA, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Hege
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Dogan
authors.affiliation: Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Sotomayor
authors.affiliation: Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Witzig
authors.affiliation: Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Mamta
authors.initials: M
authors.lastname: Gupta
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D056743:Cyclin D3 / Q000096:biosynthesis / Q000235:genetics; D039561:Eukaryotic Initiation Factor-4E / Q000032:analysis; D039562:Eukaryotic Initiation Factor-4F / Q000037:antagonists & inhibitors* / Q000502:physiology; D039603:Eukaryotic Initiation Factor-4G / Q000032:analysis; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D011719:Pyrazines / Q000494:pharmacology*; D012315:RNA Caps / Q000378:metabolism*; D034622:RNA Interference; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014410:Tumor Stem Cell Assay
chemical_list: C588406:6-(4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo(4,5-b)pyrazin-2(3H)-one; D048868:Adaptor Proteins, Signal Transducing; C534696:CCND3 protein, human; D018797:Cell Cycle Proteins; D056743:Cyclin D3; C087000:EIF4EBP1 protein, human; C113920:EIF4G1 protein, human; D039561:Eukaryotic Initiation Factor-4E; D039562:Eukaryotic Initiation Factor-4F; D039603:Eukaryotic Initiation Factor-4G; D007093:Imidazoles; C489427:MYC protein, human; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011719:Pyrazines; D012315:RNA Caps; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: CC214-1; dual mTOR inhibitors; eIF4E; lymphoma; translation initiation complex
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