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 incr eased level of bone resorption. One important mediator of bone remodelling, insulin-like growth factor (IGF-I), has been shown to stimulate the prolif eration 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 prolifera tion factor as IL-6. We demonstrated that IGF-I functions independently of the IL-6 transducer gp130 and that these two cytokines have additive effect s. Moreover, inhibition of the IGF-I pathway did not modulate the prolifera tive effect of IL-6. Accordingly, we found that IL-6 and IGF-I activated di stinct downstream signalling molecules: IL-6 activated STAT3 phosphorylatio n, whereas IGF-I treatment resulted in the phosphorylation of IRS-1. Intere stingly, these signalling pathways appear to converge as both cytokines act ivated the ras/MAPK pathway. Thus, IGF-I acts as a potent survival and prol iferation factor for myeloma cells by stimulating an IL-6-independent signa lling cascade. These data, together with the finding that, in vivo, IGF-I i s normally expressed in close proximity to myeloma cells within the bone ma trix, strongly suggest a role for this cytokine in the pathophysiology of m ultiple myeloma.