title: HGF and IGF-1 synergize with SDF-1α in promoting migration of myeloma cells by cooperative activation of p21-activated kinase.
abstract: Stromal-derived factor (SDF)-1α, insulin-like growth factor (IGF)-1 and hepatocyte growth factor (HGF) are potent mediators of cell migration. We studied the effect of combinations of these cytokines on the migration of myeloma cells. When SDF-1α was combined with either HGF or IGF-1, we found a striking synergy in the cytokines' ability to guide cells across a transwell membrane. Between HGF and IGF-1 there was no cooperativity. However, the effects of HGF and IGF-1 were not redundant. HGF and SDF-1 caused concentration gradient-directed migration, as opposed to IGF-1, which apparently caused randomly directed cell movement. The SDF-1α-driven migration of JJN-3 cells, a myeloma cell line secreting large amounts of HGF, was reduced when JJN-3 cells were given an inhibitor of the HGF receptor, demonstrating a cooperative activity between autocrine HGF and exogenous SDF-1α. There was a clear positive correlation between the degree of cytokine-induced migration and phosphorylation of p21-activated kinase (PAK) both in primary myeloma cells and in cell lines including INA-6 and IH-1. Downregulation of PAK with small interfering RNA in INA-6 cells resulted in decreased cytokine-driven migration. This study shows synergy between SDF-1α and HGF/IGF-1 in inducing migration of myeloma cells, yet each cytokine has distinct properties in the way it regulates cell migration. These findings are likely to be of clinical relevance because multiple myeloma cells are located in an environment containing HGF and IGF-1 and are exposed to an SDF-1α gradient between the bone marrow and peripheral blood.
authors.affiliation: KG Jebsen Center for Myeloma Research and Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. Torstein.Ro@ntnu.no
authors.forename: Torstein Baade
authors.initials: TB
authors.lastname: Rø
authors.forename: Toril
authors.initials: T
authors.lastname: Holien
authors.forename: Unn-Merete
authors.initials: UM
authors.lastname: Fagerli
authors.forename: Håkon
authors.initials: H
authors.lastname: Hov
authors.forename: Kristine
authors.initials: K
authors.lastname: Misund
authors.forename: Anders
authors.initials: A
authors.lastname: Waage
authors.forename: Anders
authors.initials: A
authors.lastname: Sundan
authors.forename: Randi Utne
authors.initials: RU
authors.lastname: Holt
authors.forename: Magne
authors.initials: M
authors.lastname: Børset
mesh_terms: D019898:Autocrine Communication; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004789:Enzyme Activation; D017228:Hepatocyte Growth Factor / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology* / Q000502:physiology; D009101:Multiple Myeloma / Q000473:pathology*; D009363:Neoplasm Proteins / Q000502:physiology; D019859:Proto-Oncogene Proteins c-met / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; C066855:HGF protein, human; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D011993:Recombinant Fusion Proteins; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I; D019859:Proto-Oncogene Proteins c-met; C515903:PAK1 protein, human; C515907:PAK2 protein, human; D054462:p21-Activated Kinases