Insulin-like growth factor induces the survival and proliferation of myeloma cells through an interleukin-6-independent transduction pathway

Br J Haematol. 2000 Nov;111(2):626-34. doi: 10.1046/j.1365-2141.2000.02364.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Blotting, Western
  • Cell Division / drug effects
  • Cell Line
  • DNA / biosynthesis
  • DNA-Binding Proteins / metabolism
  • Flow Cytometry
  • Humans
  • Insulin Receptor Substrate Proteins
  • Insulin-Like Growth Factor I / pharmacology*
  • Interleukin-6 / immunology*
  • MAP Kinase Signaling System / drug effects
  • Multiple Myeloma / immunology*
  • Phosphoproteins / metabolism
  • Precipitin Tests
  • STAT3 Transcription Factor
  • Signal Transduction / drug effects*
  • Stimulation, Chemical
  • Trans-Activators / metabolism


  • DNA-Binding Proteins
  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Interleukin-6
  • Phosphoproteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Trans-Activators
  • Insulin-Like Growth Factor I
  • DNA