This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lovat, P. E. Articles by Redfern, C. P.F. Search for Related Content PubMed PubMed Citation Articles by Lovat, P. E. Articles by Redfern, C. P.F.

Increasing Melanoma Cell Death Using Inhibitors of Protein Disulfide Isomerases to Abrogate Survival Responses to Endoplasmic Reticulum Stress

¹ Dermatological Sciences, School of Clinical and Laboratory Sciences and ² Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom; ³ L'Spallanzani, National Institute for Infectious Disease; and ⁴ University of Tor Vergata, Rome, Italy

Requests for reprints: Christopher Redfern, Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne NE2 4HH, United Kingdom. Phone: 44-191-246-4416; Fax: 44-191-246-4301; E-mail: chris.redfern{at}ncl.ac.uk.

Key Words: Apoptosis • Endoplasmic reticulum stress • protein disulfide isomerase inhibitors

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. [Cancer Res 2008;68(13):5363–8]

This article has been cited by other articles:

				V. Gillardin, F. Silvestre, M. Dieu, E. Delaive, M. Raes, J.-P. Thome, and P. Kestemont Protein Expression Profiling in the African Clawed Frog Xenopus laevis Tadpoles Exposed to the Polychlorinated Biphenyl Mixture Aroclor 1254 Mol. Cell. Proteomics, April 1, 2009; 8(4): 596 - 611. [Abstract] [Full Text] [PDF]

				D. S. Hill, S. Martin, J. L. Armstrong, R. Flockhart, J. J. Tonison, D. G. Simpson, M. A. Birch-Machin, C. P.F. Redfern, and P. E. Lovat Combining the Endoplasmic Reticulum Stress-Inducing Agents Bortezomib and Fenretinide as a Novel Therapeutic Strategy for Metastatic Melanoma Clin. Cancer Res., February 15, 2009; 15(4): 1192 - 1198. [Abstract] [Full Text] [PDF]