Insulin-like growth factor induces the survival and proliferation of myeloma cells through an interleukin-6-independent transduction pathway.
Multiple myeloma (MM) is a B-cell neoplasia that is associated with an increased level of bone resorption. One important mediator of bone remodelling, insulin-like growth factor (IGF-I), has been shown to stimulate the proliferation of human myeloma cells. However, the mechanisms of action of IGF-I in these cells have not been determined. Using interleukin (IL)-6-dependent myeloma cell lines, we show IGF-I to be as potent a survival and proliferation factor as IL-6. We demonstrated that IGF-I functions independently of the IL-6 transducer gp130 and that these two cytokines have additive effects. Moreover, inhibition of the IGF-I pathway did not modulate the proliferative effect of IL-6. Accordingly, we found that IL-6 and IGF-I activated distinct downstream signalling molecules: IL-6 activated STAT3 phosphorylation, whereas IGF-I treatment resulted in the phosphorylation of IRS-1. Interestingly, these signalling pathways appear to converge as both cytokines activated the ras/MAPK pathway. Thus, IGF-I acts as a potent survival and proliferation factor for myeloma cells by stimulating an IL-6-independent signalling cascade. These data, together with the finding that, in vivo, IGF-I is normally expressed in close proximity to myeloma cells within the bone matrix, strongly suggest a role for this cytokine in the pathophysiology of multiple myeloma.
Ferlin
M
M
INSERM U475 and Unit for Cellular Therapy, CHU Montpellier, France, and Institut de Génétique Moléculaire, UMR5535, IFR-24, Montpellier, France.
Noraz
N
N
Hertogh
C
C
Brochier
J
J
Taylor
N
N
Klein
B
B
D017209:Apoptosis; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D015850:Interleukin-6 / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009101:Multiple Myeloma / Q000276:immunology*; D010750:Phosphoproteins / Q000378:metabolism; D011233:Precipitin Tests; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D013268:Stimulation, Chemical; D015534:Trans-Activators / Q000378:metabolism
D004268:DNA-Binding Proteins; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D015850:Interleukin-6; D010750:Phosphoproteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D007334:Insulin-Like Growth Factor I; D004247:DNA