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.