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Lookup NU author(s): Professor Penny Lovat, Dr Jane Renwick, Shaun Martin, Dr David Hill, Professor Mark Birch-MachinORCiD, Dr Chris RedfernORCiD
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Exploiting vulnerabilities in the intracellular signaling pathways of tumor cells is a key strategy for the development of new drugs. The activation of cellular stress responses mediated by the endoplasmic reticulum (ER) allows cancer cells to survive outside their normal environment. Many proteins that protect cells against ER stress are active as protein disulfide isomerases (PDI) and the aim of this study was to test the hypothesis that apoptosis in response to ER stress can be increased by inhibiting PDI activity. We show that the novel chemotherapeutic drugs fenretinide and velcade induce ER stress-mediated apoptosis in melanoma cells. Both stress response and apoptosis were enhanced by the PDI inhibitor bacitracin. Overexpression of the main cellular PDI, procollagen-proline, 2-oxoglutarate-4-dioxygenase β subunit (P4HB), resulted in increased PDI activity and abrogated the apoptosis-enhancing effect of bacitracin. In contrast, overexpression of a mutant P4HB lacking PDI activity did not increase cellular PDI activity or block the effects of bacitracin. These results show that inhibition of PDI activity increases apoptosis in response to agents which induce ER stress and suggest that the development of potent, small-molecule PDI inhibitors has significant potential as a powerful tool for enhancing the efficacy of chemotherapy in melanoma. ©2008 American Association for Cancer Research.
Author(s): Lovat PE, Corazzari M, Armstrong JL, Martin S, Pagliarini V, Hill DS, Brown A, Piacentini M, Birch-Machin MA, Redfern CPF
Publication type: Article
Publication status: Published
Journal: Cancer Research
Year: 2008
Volume: 68
Issue: 13
Pages: 5363-5369
Print publication date: 01/07/2008
ISSN (print): 0008-5472
ISSN (electronic): 1538-7445
Publisher: American Association for Cancer Research
URL: http://dx.doi.org/10.1158/0008-5472.CAN-08-0035
DOI: 10.1158/0008-5472.CAN-08-0035
PubMed id: 18593938
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