title: Therapeutic enhancement of ER stress by insulin-like growth factor I sensitizes myeloma cells to proteasomal inhibitors.
abstract: OBJECTIVE
  Multiple myeloma is a clonal plasma cell disorder in which growth and proliferation are linked to a variety of growth factors, including insulin-like growth factor type I (IGF-I). Bortezomib, the first-in-class proteasome inhibitor, has displayed significant antitumor activity in multiple myeloma.
  
  
  METHODS
  We analyzed the impact of IGF-I combined with proteasome inhibitors on multiple myeloma cell lines in vivo and in vitro as well as on fresh human myeloma cells.
  
  
  RESULTS
  Our study shows that IGF-I enhances the cytotoxic effect of proteasome inhibitors against myeloma cells. The effect of bortezomib on the content of proapoptotic proteins such as Bax, Bad, Bak, and BimS and antiapoptotic proteins such as Bcl-2, Bcl-XL, XIAP, Bfl-1, and survivin was enhanced by IGF-I. The addition of IGF-I to bortezomib had a minor effect on NF-κB signaling in MM.1S cells while strongly enhancing reticulum stress. This resulted in an unfolded protein response (UPR), which was required for the potentiating effect of IGF-I on bortezomib cytotoxicity as shown by siRNA-mediated inhibition of GADD153 expression.
  
  
  CONCLUSIONS
  These results suggest that the high baseline level of protein synthesis in myeloma can be exploited therapeutically by combining proteasome inhibitors with IGF-I, which possesses a "priming" effect on myeloma cells for this family of compounds.
authors.affiliation: Université de Lyon, Lyon, France.
authors.forename: Inès
authors.initials: I
authors.lastname: Tagoug
authors.forename: Lars Petter
authors.initials: LP
authors.lastname: Jordheim
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Herveau
authors.forename: Eva-Laure
authors.initials: EL
authors.lastname: Matera
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Huber
authors.forename: Kamel
authors.initials: K
authors.lastname: Chettab
authors.forename: Serge
authors.initials: S
authors.lastname: Manié
authors.forename: Charles
authors.initials: C
authors.lastname: Dumontet
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D014176:Protein Biosynthesis / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D001897:Boronic Acids; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011719:Pyrazines; D007334:Insulin-Like Growth Factor I; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex