title: Signal transduction and downregulation of C-MET in HGF stimulated low and highly metastatic human osteosarcoma cells.
abstract: The poor outcome of osteosarcoma (OS), particularly in patients with metastatic disease and a five-year survival rate of only 20%, asks for more effective therapeutic strategies targeting malignancy-promoting mechanisms. Dysregulation of C-MET, its ligand hepatocyte growth factor (HGF) and the fusion oncogene product TPR-MET, first identified in human MNNG-HOS OS cells, have been described as cancer-causing factors in human cancers. Here, the expression of these molecules at the mRNA and the protein level and of HGF-stimulated signaling and downregulation of C-MET was compared in the parental low metastatic HOS and MG63 cell lines and the respective highly metastatic MNNG-HOS and 143B and the MG63-M6 and MG63-M8 sublines. Interestingly, expression of TPR-MET was only observed in MNNG-HOS cells. HGF stimulated the phosphorylation of Akt and Erk1/2 in all cell lines investigated, but phospho-Stat3 remained at basal levels. Downregulation of HGF-stimulated Akt and Erk1/2 phosphorylation was much faster in the HGF expressing MG63-M8 cells than in HOS cells. Degradation of HGF-activated C-MET occurred predominantly through the proteasomal and to a lesser extent the lysosomal pathway in the cell lines investigated. Thus, HGF-stimulated Akt and Erk1/2 signaling as well as proteasomal degradation of HGF activated C-MET are potential therapeutic targets in OS.
authors.affiliation: Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich, Switzerland. Electronic address: khusmann@research.balgrist.ch.
authors.forename: Knut
authors.initials: K
authors.lastname: Husmann
authors.affiliation: Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich, Switzerland; Division of Plastic Surgery and Hand Surgery, Department of Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Ducommun
authors.affiliation: Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich, Switzerland.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Sabile
authors.affiliation: Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich, Switzerland.
authors.forename: Else-Marie
authors.initials: EM
authors.lastname: Pedersen
authors.affiliation: Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Born
authors.affiliation: Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Fuchs
mesh_terms: D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology / Q000556:secondary*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D017228:Hepatocyte Growth Factor; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases
keywords: C-MET; Osteosarcoma; Signal transduction; TPR-MET