Nelfinavir induces the unfolded protein response in ovarian cancer cells, resulting in ER vacuolization, cell cycle retardation and apoptosis.
Proteasome inhibitors and protease inhibitors are currently being discussed to be useful to sensitize drug-resistant cancer cells to chemotherapeutic agents or to act independently as single agents on drug-resistant cancer cells. We tested the effect of the clinically applied HIV protease inhibitor nelfinavir on ovarian cancer cells. Nelfinavir efficiently induced cell death in carboplatin-sensitive (SKOV3, OV-GH-5) and carboplatin-resistant (OVCAR3, OV-GH-1) ovarian cancer cell lines as well as in cancer biopsies and ascites samples from patients with recurrent ovarian cancer. Nelfinavir significantly changed the morphology of ovarian cancer cells, resulting in formation of large ER-derived vacuoles and induced upregulation of the hsp70 heat shock family member BiP (GRP78) which accumulated within swollen ER membranes. Upregulation of BiP and phosphorylation of eIF2alpha indicated induction of the unfolded protein response, which can cause cell cycle arrest and apoptosis. Correspondingly, we observed downregulation of cell cycle regulatory proteins after nelfinavir treatment, especially that of cyclin D3, and induction of apoptosis as confirmed by annexin binding. Because nelfinavir represents an already approved drug for use in humans with HIV infection, it could rapidly be tested in clinical studies as a potential treatment strategy against drug-resistant ovarian cancer.
Brüning
Ansgar
A
University Hospital Munich, Department of Obstetrics/Gynecology, Maistrasse 11, München 80337, Germany. ansgar.bruening@med.uni-muenchen.de
Burger
Petra
P
Vogel
Marianne
M
Rahmeh
Martina
M
Gingelmaiers
Andrea
A
Friese
Klaus
K
Lenhard
Miriam
M
Burges
Alexander
A
D017209:Apoptosis / Q000187:drug effects*; D018929:Cell Culture Techniques; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D056743:Cyclin D3 / Q000096:biosynthesis; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D006801:Humans; D019888:Nelfinavir / Q000494:pharmacology*; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D017510:Protein Folding; D014617:Vacuoles / Q000473:pathology
C534696:CCND3 protein, human; D056743:Cyclin D3; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D017320:HIV Protease Inhibitors; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D019888:Nelfinavir