Targeting GRP78 to enhance melanoma cell death

Authors

  • Shaun Martin,

    1.  Northern Institute of Cancer Research and Newcastle Cancer Centre, Newcastle University, Newcastle upon Tyne, UK
    2.  Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
    Search for more papers by this author
  • David S. Hill,

    1.  Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
    Search for more papers by this author
  • James C. Paton,

    1.  Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, Australia
    Search for more papers by this author
  • Adrienne W. Paton,

    1.  Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, Australia
    Search for more papers by this author
  • Mark A. Birch-Machin,

    1.  Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
    Search for more papers by this author
  • Penny E. Lovat,

    1.  Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
    Search for more papers by this author
  • Chris P.F. Redfern

    1.  Northern Institute of Cancer Research and Newcastle Cancer Centre, Newcastle University, Newcastle upon Tyne, UK
    Search for more papers by this author

Chris Redfern, email: chris.redfern@ncl.ac.uk

Summary

Targeting endoplasmic reticulum stress-induced apoptosis may offer an alternative therapeutic strategy for metastatic melanoma. Fenretinide and bortezomib induce apoptosis of melanoma cells but their efficacy may be hindered by the unfolded protein response, which promotes survival by ameliorating endoplasmic reticulum stress. The aim of this study was to test the hypothesis that inhibition of GRP78, a vital unfolded protein response mediator, increases cell death in combination with endoplasmic reticulum stress-inducing agents. Down-regulation of GRP78 by small-interfering RNA increased fenretinide- or bortezomib-induced apoptosis. Treatment of cells with a GRP78-specific subtilase toxin produced a synergistic enhancement with fenretinide or bortezomib. These data suggest that combining endoplasmic reticulum stress-inducing agents with strategies to down-regulate GRP78, or other components of the unfolded protein response, may represent a novel therapeutic approach for metastatic melanoma.

Ancillary