title: Nelfinavir induces mitochondria protection by ERK1/2-mediated mcl-1 stabilization that can be overcome by sorafenib.
abstract: The HIV protease inhibitor nelfinavir is an investigational drug for cancer treatment. We have previously demonstrated induction of apoptosis by nelfinavir even in chemo-resistant ovarian cancer cells. In contrast to the pro-apoptotic effect of nelfinavir on human cancer cells, we noticed a significant upregulation of the anti-apoptotic mitochondrial membrane protein mcl-1 by nelfinavir, resulting in a mitochondria-independent induction of apoptosis. Upregulation of mcl-1 was associated with enhanced phosphorylation of both mcl-1 and of ERK1/2 (extracellular signal-regulated kinases 1/2). ERK1/2 enhanced stability of mcl-1 protein expression by serine-163 phosphorylation. The combination of nelfinavir with sorafenib, a clinically applied inhibitor of the RAS/RAF/ERK1/2 pathway, inhibited nelfinavir-induced ERK1/2 activation and mcl-1 protein upregulation. Further, the combination of nelfinavir with sorafenib induced mitochondrial membrane potential disruption and resulted in an improved activity of nelfinavir on ovarian cancer cells. Thus, a combination of these two investigational anti-cancer drugs could be of interest especially because of their unique mechanism of apoptosis induction even in otherwise chemo-resistant human cancer cells.
authors: Department of Obstetrics/Gynaecology, Molecular Biology Laboratory, Ludwig-Maximilians University Munich, Munich, Germany. ansgar231@web.de
authors: Ansgar
authors: A
authors: Brüning
authors: Petra
authors: P
authors: Burger
authors: Marianne
authors: M
authors: Vogel
authors: Andrea
authors: A
authors: Gingelmaier
authors: Klaus
authors: K
authors: Friese
authors: Alexander
authors: A
authors: Burges
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001557:Benzenesulfonates / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019888:Nelfinavir / Q000494:pharmacology*; D009536:Niacinamide / Q000031:analogs & derivatives; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000473:pathology; D010671:Phenylurea Compounds; D010766:Phosphorylation / Q000187:drug effects; D011419:Propidium / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D000077157:Sorafenib
chemical_list: D017304:Annexin A5; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D017320:HIV Protease Inhibitors; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D009536:Niacinamide; D011419:Propidium; D000077157:Sorafenib; D048049:Extracellular Signal-Regulated MAP Kinases; D019888:Nelfinavir