title: Insulin is a potent myeloma cell growth factor through insulin/IGF-1 hybrid receptor activation.
abstract: Insulin and insulin growth factor type 1 (IGF-1) and their receptors are closely related molecules, but both factors bind to the receptor of the other one with a weak affinity. No study has presently documented a role of insulin as a myeloma growth factor (MGF) for human multiple myeloma cells (MMCs), whereas many studies have concluded that IGF-1 is a major MGF. IGF-1 receptor (IGF-1R) is aberrantly expressed by MMCs in association with a poor prognosis. In this study we show that insulin receptor (INSR) is increased throughout normal plasma cell differentiation. INSR gene is also expressed by MMCs of 203/206 newly diagnosed patients. Insulin is an MGF as potent as IGF-1 at physiological concentrations and requires the presence of insulin/IGF-1 hybrid receptors, stimulating INSR(+)IGF-1R(+) MMCs, unlike INSR(+)IGF-1R(-) or INSR(-)IGF-1R(-) MMCs. Immunoprecipitation experiments indicate that INSR is linked with IGF-1R in MMCs and that insulin induces both IGF-1R and INSR phosphorylations and vice versa. In conclusion, we demonstrate for the first time that insulin is an MGF as potent as IGF-1 at physiological concentrations and its activity necessitates insulin/IGF-1 hybrid receptor activation. Further therapeutic strategies targeting the IGF/IGF-1R pathway have to take into account neutralizing the IGF-1R-mediated insulin MGF activity.
authors.affiliation: INSERM, U847, Montpellier, France.
authors.forename: A C
authors.initials: AC
authors.lastname: Sprynski
authors.forename: D
authors.initials: D
authors.lastname: Hose
authors.forename: A
authors.initials: A
authors.lastname: Kassambara
authors.forename: L
authors.initials: L
authors.lastname: Vincent
authors.forename: M
authors.initials: M
authors.lastname: Jourdan
authors.forename: J F
authors.initials: JF
authors.lastname: Rossi
authors.forename: H
authors.initials: H
authors.lastname: Goldschmidt
authors.forename: B
authors.initials: B
authors.lastname: Klein
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D007700:Kinetics; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology*; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D017526:Receptor, IGF Type 1 / Q000276:immunology / Q000302:isolation & purification / Q000502:physiology*; D011972:Receptor, Insulin / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
chemical_list: D000911:Antibodies, Monoclonal; D006133:Growth Substances; D007328:Insulin; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin