This work was supported by grants from the Norwegian Cancer Society, the Norwegian Research Council, The Cancer Fund at St Olav University Hospital University Hospital and the Grieg Foundation.
c-Met signaling promotes IL-6-induced myeloma cell proliferation
Version of Record online: 6 JAN 2009
© 2009 The Authors. Journal compilation © 2009 Blackwell Munksgaard
European Journal of Haematology
Volume 82, Issue 4, pages 277–287, April 2009
How to Cite
Hov, H., Tian, E., Holien, T., Holt, R. U., Våtsveen, T. K., Fagerli, U.-M., Waage, A., Børset, M. and Sundan, A. (2009), c-Met signaling promotes IL-6-induced myeloma cell proliferation. European Journal of Haematology, 82: 277–287. doi: 10.1111/j.1600-0609.2009.01212.x
Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.
- Issue online: 19 FEB 2009
- Version of Record online: 6 JAN 2009
- Accepted for publication 22 December 2008
- multiple myeloma;
- receptor tyrosine kinase;
- intracellular signaling
Objectives: Hepatocyte growth factor (HGF) is a constituent of the myeloma microenvironment and is elevated in sera from myeloma patients compared to healthy individuals. Increased levels of serum HGF predict a poor prognosis. It has previously been shown by us and others HGF can act as a growth factor to myeloma cells in vitro although these effects have been moderate. We therefore wanted to investigate if HGF could influence the effects of interleukin (IL)-6.
Methods: Myeloma cell lines and primary samples were tested for the combined effects of IL-6 and HGF in inducing DNA synthesis and migration. Expression levels of c-Met protein were analysed by Western blotting and flow cytometry. Signaling pathways were examined by Western blotting using phosphospecific antibodies and a Ras-GTP pull down assay.
Results: HGF potentiated IL-6-induced growth in human myeloma cell lines and in purified primary myeloma cells. There was also cooperation between HGF and IL-6 in induction of migration. There seemed to be two explanations for this synergy. IL-6-treatment increased the expression of c-Met making cells HGF responsive, and IL-6 was dependent on c-Met signaling in activating both Ras and p44/42 MAPK by a mechanism involving the tyrosine phosphatase Shp2.
Conclusions: The results indicate that besides from being a myeloma growth factor alone, HGF can also potentiate the effects of IL-6 in myeloma proliferation and migration. Thus, c-Met signaling could be a target for therapy of multiple myeloma.