Signal transduction and downregulation of C-MET in HGF stimulated low and highly metastatic human osteosarcoma cells

Husmann, Knut; Ducommun, Pascal; Sabile, Adam A.; Pedersen, Else-Marie; Born, Walter; Fuchs, Bruno

doi:10.1016/J.BBRC.2015.07.108

Title: Signal transduction and downregulation of C-MET in HGF stimulated low and highly metastatic human osteosarcoma cells

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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. -more »« less

Authors:

Husmann, Knut ^[1]; Ducommun, Pascal ^[1]; Sabile, Adam A.; Pedersen, Else-Marie; Born, Walter; Fuchs, Bruno ^[1]

Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich (Switzerland)

Publication Date:: Fri Sep 04 00:00:00 EDT 2015

OSTI Identifier:: 22462241

Resource Type:: Journal Article

Journal Name:: Biochemical and Biophysical Research Communications

Additional Journal Information:: Journal Volume: 464; Journal Issue: 4; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES; COMPARATIVE EVALUATIONS; GROWTH FACTORS; HUMAN POPULATIONS; LIGANDS; MESSENGER-RNA; METASTASES; ONCOGENES; OSTEOSARCOMAS; PATIENTS; PHOSPHORYLATION; SIGNALS

Citation Formats


                    Husmann, Knut, Ducommun, Pascal, Division of Plastic Surgery and Hand Surgery, Department of Surgery, University Hospital Zurich, Zurich, Sabile, Adam A., Pedersen, Else-Marie, Born, Walter, and Fuchs, Bruno. Signal transduction and downregulation of C-MET in HGF stimulated low and highly metastatic human osteosarcoma cells.  United States: N. p., 2015. 
        Web.  doi:10.1016/J.BBRC.2015.07.108.

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                    Husmann, Knut, Ducommun, Pascal, Division of Plastic Surgery and Hand Surgery, Department of Surgery, University Hospital Zurich, Zurich, Sabile, Adam A., Pedersen, Else-Marie, Born, Walter, & Fuchs, Bruno. Signal transduction and downregulation of C-MET in HGF stimulated low and highly metastatic human osteosarcoma cells.  United States.  https://doi.org/10.1016/J.BBRC.2015.07.108

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                    Husmann, Knut, Ducommun, Pascal, Division of Plastic Surgery and Hand Surgery, Department of Surgery, University Hospital Zurich, Zurich, Sabile, Adam A., Pedersen, Else-Marie, Born, Walter, and Fuchs, Bruno. 2015.  
        "Signal transduction and downregulation of C-MET in HGF stimulated low and highly metastatic human osteosarcoma cells".  United States.  https://doi.org/10.1016/J.BBRC.2015.07.108.

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@article{osti_22462241,

  title        = {Signal transduction and downregulation of C-MET in HGF stimulated low and highly metastatic human osteosarcoma cells},

  author       = {Husmann, Knut and Ducommun, Pascal and Division of Plastic Surgery and Hand Surgery, Department of Surgery, University Hospital Zurich, Zurich and Sabile, Adam A. and Pedersen, Else-Marie and Born, Walter and Fuchs, Bruno},

  abstractNote = {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. - Highlights: • Expression of TPR-MET was only observed in MNNG-HOS cells. • HGF stimulated the phosphorylation of Akt and Erk1/2 but not of Stat3 in osteosarcoma cell lines. • Degradation of HGF-activated C-MET occurred predominantly through the proteasomal pathway.},

  doi          = {10.1016/J.BBRC.2015.07.108},

  url          = {https://www.osti.gov/biblio/22462241},
  journal      = {Biochemical and Biophysical Research Communications},

  issn         = {0006-291X},

  number       = 4,

  volume       = 464,

  place        = {United States},

  year         = {Fri Sep 04 00:00:00 EDT 2015},

  month        = {Fri Sep 04 00:00:00 EDT 2015}

}

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