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

• Published in: Cancer research (Chicago, Ill.) Vol. 68; no. 13; pp. 5363 - 5369
• Main Authors: LOVAT, Penny E, CORAZZARI, Marco, ARMSTRONG, Jane L, MARTIN, Shaun, PAGLIARINI, Vittoria, HILL, David, BROWN, Anna M, PIACENTINI, Mauro, BIRCH-MACHIN, Mark A, REDFERN, Christopher P. F
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-07-2008
• Subjects: Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis - drug effects; Bacitracin - administration & dosage; Bacitracin - pharmacology; Biological and medical sciences; Boronic Acids - administration & dosage; Boronic Acids - pharmacology; Bortezomib; Cell Death - drug effects; Cell Survival - drug effects; Dermatology; Drug Evaluation, Preclinical; Drug Synergism; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - pathology; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - pharmacology; Fenretinide - administration & dosage; Fenretinide - pharmacology; Humans; Medical sciences; Melanoma - drug therapy; Melanoma - pathology; Oxidative Stress - drug effects; Oxidative Stress - physiology; Pharmacology. Drug treatments; Protein Disulfide-Isomerases - antagonists & inhibitors; Pyrazines - administration & dosage; Pyrazines - pharmacology; Treatment Outcome; Tumor Cells, Cultured; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Intramolecular oxidoreductases; Enzyme; Malignant tumor; Survival; Stress; Isomerases; Cell death; Malignant melanoma; Protein disulfide-isomerase; Inhibitor; Endoplasmic reticulum; Cancer; Apoptosis
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-0035

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 beta 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.