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.
Insulin-like growth factor induces the survival and proliferation of myeloma cells through an interleukin-6-independent transduction pathway
Ferlin, M.; Noraz, N.; Hertogh, C.; Brochier, J.; Taylor, N.; Klein, B.
Br J Haematol
2000-11 / vol 111 / pages 626-34
Humans; MAP Kinase Signaling System/drug effects; Flow Cytometry; Precipitin Tests; Cell Line; DNA/biosynthesis; Blotting, Western; Phosphoproteins/metabolism; Signal Transduction/*drug effects; Apoptosis; Trans-Activators/metabolism; DNA-Binding Proteins/metabolism; Cell Division/drug effects; Insulin-Like Growth Factor I/*pharmacology; Interleukin-6/*immunology; Multiple Myeloma/*immunology; STAT3 Transcription Factor; Stimulation, Chemical