title: The cap-translation inhibitor 4EGI-1 induces apoptosis in multiple myeloma through Noxa induction.
abstract: BACKGROUND
  Cancer cells are frequently addicted to deregulated oncogenic protein translation. The small molecule 4EG-I selectively inhibits the cap-dependent translation of mRNAs. As multiple myeloma is an incurable disease that requires new therapeutic approaches, we investigated whether targeting the translation initiation pathway could be a target for myeloma therapy.
  
  
  METHODS
  Six myeloma cell lines and primary samples were included in this study. The 4EGI-1 effect was determined by AnnexinV staining and caspase activation. Modification of Bcl-2 protein expression was analysed, and the significance of modified proteins was analysed by knock-down experiments.
  
  
  RESULTS
  We demonstrated that 4EGI-1 impaired the assembly of the eIF4F complex and decreased the expression of the eIF4E-regulated proteins in myeloma cells. Furthermore, we showed that 4EGI-1 induced strong apoptosis in five out of six myeloma cell lines. Apoptosis is associated with the activation of the intrinsic mitochondrial pathway. The 4EGI-1 triggered Noxa induction only in cells undergoing apoptosis through endoplasmic reticulum (ER) stress. Furthermore, Noxa silencing prevented myeloma cells from 4EGI-1-induced apoptosis. Finally, Noxa induction led to a disruption of Mcl-1/Bim complexes in parallel to the generation of 'Mcl-1-free Noxa'.
  
  
  CONCLUSIONS
  Our results suggested that the use of inhibitors that directly target the translation initiation complex eIF4F could represent a potential novel approach for multiple myeloma therapy.
authors.affiliation: Inserm, U892, Univ Nantes, CNRS, UMR 6299, Nantes, F-44000, France.
authors.forename: G
authors.initials: G
authors.lastname: Descamps
authors.forename: P
authors.initials: P
authors.lastname: Gomez-Bougie
authors.forename: J
authors.initials: J
authors.lastname: Tamburini
authors.forename: A
authors.initials: A
authors.lastname: Green
authors.forename: D
authors.initials: D
authors.lastname: Bouscary
authors.forename: S
authors.initials: S
authors.lastname: Maïga
authors.forename: P
authors.initials: P
authors.lastname: Moreau
authors.forename: S
authors.initials: S
authors.lastname: Le Gouill
authors.forename: C
authors.initials: C
authors.lastname: Pellat-Deceunynck
authors.forename: M
authors.initials: M
authors.lastname: Amiot
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D039562:Eukaryotic Initiation Factor-4F / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D006835:Hydrazones; D008565:Membrane Proteins / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009574:Nitro Compounds / Q000494:pharmacology*; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: C517852:4EGI-1 compound; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D039562:Eukaryotic Initiation Factor-4F; D006835:Hydrazones; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009574:Nitro Compounds; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013844:Thiazoles