Nelfinavir induces mitochondria protection by ERK1/2-mediated mcl-1 stabilization that can be overcome by sorafenib.
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.
Brüning
Ansgar
A
Department of Obstetrics/Gynaecology, Molecular Biology Laboratory, Ludwig-Maximilians University Munich, Munich, Germany. ansgar231@web.de
Burger
Petra
P
Vogel
Marianne
M
Gingelmaier
Andrea
A
Friese
Klaus
K
Burges
Alexander
A
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
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