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Targeting GRP78 to enhance melanoma cell death

Lookup NU author(s): Shaun Martin, Dr David Hill, Professor Mark Birch-MachinORCiD, Professor Penny Lovat, Dr Chris RedfernORCiD


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P>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.

Publication metadata

Author(s): Martin S, Hill DS, Paton JC, Paton AW, Birch-Machin MA, Lovat PE, Redfern CPF

Publication type: Article

Publication status: Published

Journal: Pigment Cell and Melanoma Research

Year: 2010

Volume: 23

Issue: 5

Pages: 675-682

Print publication date: 12/07/2010

ISSN (print): 1755-1471

ISSN (electronic): 1755-148X

Publisher: Wiley-Blackwell


DOI: 10.1111/j.1755-148X.2010.00731.x


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