Targeting GRP78 to enhance melanoma cell death.
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.
Martin
Shaun
S
Northern Institute of Cancer Research and Newcastle Cancer Centre, Newcastle University, Newcastle upon Tyne, UK.
Hill
David S
DS
Paton
James C
JC
Paton
Adrienne W
AW
Birch-Machin
Mark A
MA
Lovat
Penny E
PE
Redfern
Chris P F
CP
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D017313:Fenretinide / Q000494:pharmacology / Q000627:therapeutic use; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000378:metabolism; D056811:Unfolded Protein Response
D000970:Antineoplastic Agents; D001897:Boronic Acids; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D011719:Pyrazines; D034741:RNA, Small Interfering; D017313:Fenretinide; D000069286:Bortezomib