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Targeting GRP78 to enhance melanoma cell death
Author(s) -
Martin Shaun,
Hill David S.,
Paton James C.,
Paton Adrienne W.,
BirchMachin Mark A.,
Lovat Penny E.,
Redfern Chris P.F.
Publication year - 2010
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/j.1755-148x.2010.00731.x
Subject(s) - endoplasmic reticulum , unfolded protein response , bortezomib , fenretinide , apoptosis , cancer research , programmed cell death , microbiology and biotechnology , vemurafenib , melanoma , biology , medicine , multiple myeloma , immunology , cell culture , biochemistry , retinoid , retinoic acid , genetics , metastatic melanoma
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.