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Research Paper

Nelfinavir induces the unfolded protein response in ovarian cancer cells, resulting in ER vacuolization, cell cycle retardation and apoptosis

Ansgar Brüning, Petra Burger, Marianne Vogel, Martina Rahmeh, Andrea Gingelmaier, Klaus Friese, Miriam Lenhard and Alexander Burges

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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.

Authors

Ansgar Brüning

University Hospital Munich, Department of Obstetrics/Gynecology, Munich, Germany

Petra Burger

University Hospital Munich, Department of Obstetrics/Gynecology, Munich, Germany

Marianne Vogel

University Hospital Munich, Department of Obstetrics/Gynecology, Munich, Germany

Martina Rahmeh

University Hospital Munich, Department of Obstetrics/Gynecology, Munich, Germany

Andrea Gingelmaier

University Hospital Munich, Department of Obstetrics/Gynecology, Munich, Germany

Klaus Friese

University Hospital Munich, Department of Obstetrics/Gynecology, Munich, Germany

Miriam Lenhard

University Hospital Munich, Department of Obstetrics/Gynecology, Munich, Germany

Alexander Burges

University Hospital Munich, Department of Obstetrics/Gynecology, Munich, Germany

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If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.