title: Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma.
abstract: BACKGROUND
  Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage. Therefore, eIF4F translation initiation complex components are attractive therapeutic targets.
  
  
  METHODS
  Protein lysates of myeloma cells (cell lines/patients' bone marrow samples) untreated/treated with bevacizumab were assayed for eIF4GI expression, regulation (NQO1/proteosome dependent fragmentation) (WB, Dicumarol, qPCR) and targets (WB). eIF4GI was inhibited by knockdown and 4EGI-1. Cells were tested for viability (ELISA), death (FACS) and eIF4GI targets (WB).
  
  
  RESULTS
  Previously, we have shown that manipulation of VEGF in myeloma cells attenuated eIF4E dependent translation initiation. Here we assessed the significance of eIF4GI to MM cells. We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon VEGF inhibition attributed to elevated NQO1/proteasome dependent fragmentation and diminished mRNA levels. Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets (SMAD5/ERα/HIF1α/c-Myc). Finally, we showed that the small molecule 4EGI-1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma.
  
  
  CONCLUSIONS
  Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI, critical to cell phenotype, and mark it as a viable target for pharmacological intervention.
authors.affiliation: Oncogenetic Laboratory, Meir Medical Center, Kfar Saba 44281, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Oshrat
authors.initials: O
authors.lastname: Attar-Schneider
authors.affiliation: Oncogenetic Laboratory, Meir Medical Center, Kfar Saba 44281, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: druckerl@clalit.org.il.
authors.forename: Liat
authors.initials: L
authors.lastname: Drucker
authors.affiliation: Oncogenetic Laboratory, Meir Medical Center, Kfar Saba 44281, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Victoria
authors.initials: V
authors.lastname: Zismanov
authors.affiliation: Oncogenetic Laboratory, Meir Medical Center, Kfar Saba 44281, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Shelly
authors.initials: S
authors.lastname: Tartakover-Matalon
authors.affiliation: Oncogenetic Laboratory, Meir Medical Center, Kfar Saba 44281, Israel; Department of Internal Medicine, Meir Medical Center, Kfar Saba 44281, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Lishner
mesh_terms: D020533:Angiogenesis Inhibitors / Q000633:toxicity; D061067:Antibodies, Monoclonal, Humanized / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D000068258:Bevacizumab; D015536:Down-Regulation / Q000187:drug effects; D039603:Eukaryotic Initiation Factor-4G / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C517852:4EGI-1 compound; D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; C113920:EIF4G1 protein, human; D039603:Eukaryotic Initiation Factor-4G; D006835:Hydrazones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013844:Thiazoles; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex
keywords: Bevacizumab; Multiple myeloma; Translation initiation; eIF4GI