Insulin is a potent myeloma cell growth factor through insulin/IGF-1 hybrid receptor activation.
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.
Sprynski
A C
AC
INSERM, U847, Montpellier, France.
Hose
D
D
Kassambara
A
A
Vincent
L
L
Jourdan
M
M
Rossi
J F
JF
Goldschmidt
H
H
Klein
B
B
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
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