c-Met signaling promotes IL-6-induced myeloma cell proliferation.
OBJECTIVE
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.
Hov
Håkon
H
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. hakonhov@ntnu.no
Tian
Erming
E
Holien
Toril
T
Holt
Randi Utne
RU
Våtsveen
Thea K
TK
Fagerli
Unn-Merete
UM
Waage
Anders
A
Børset
Magne
M
Sundan
Anders
A
D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D016895:Culture Media, Serum-Free; D004357:Drug Synergism; D005434:Flow Cytometry; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015850:Interleukin-6 / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000473:pathology*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction
D016895:Culture Media, Serum-Free; D015850:Interleukin-6; D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met