Abstract
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.
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Acknowledgements
This work was supported by grants from the Ligue Nationale Contre le Cancer (équipe labellisée), Paris, France, from INCA (no. R07001FN) and from MSCNET European strep (no. E06005FF), the Hopp-Foundation, Germany, the University of Heidelberg, Germany, the National Centre for Tumor Diseases, Heidelberg, Germany, the Tumorzentrum Heidelberg/Mannheim, Germany. AC Sprynski is supported by Association Guillaume Espoir, St Genis Laval, France.
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Sprynski, A., Hose, D., Kassambara, A. et al. Insulin is a potent myeloma cell growth factor through insulin/IGF-1 hybrid receptor activation. Leukemia 24, 1940–1950 (2010). https://doi.org/10.1038/leu.2010.192
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DOI: https://doi.org/10.1038/leu.2010.192
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