Triggering of a novel intrinsic apoptosis pathway by the kinase inhibitor staurosporine: activation of caspase-9 in the absence of Apaf-1.

Abstract

The protein kinase inhibitor staurosporine is one of the most potent and frequently used proapoptotic stimuli, although its mechanism of action is poorly understood. Here, we show that staurosporine as well as its analog 7-hydroxystaurosporine (UCN-01) not only trigger the classical mitochondrial apoptosis pathway but, moreover, activate an additional novel intrinsic apoptosis pathway. Unlike conventional anticancer drugs, staurosporine and UCN-01 induced apoptosis in a variety of tumor cells overexpressing the apoptosis inhibitors Bcl-2 and Bcl-x(L). Furthermore, activation of this novel intrinsic apoptosis pathway by staurosporine did not rely on Apaf-1 and apoptosome formation, an essential requirement for the mitochondrial pathway. Nevertheless, as demonstrated in caspase-9-deficient murine embryonic fibroblasts, human lymphoma cells, and chicken DT40 cells, staurosporine-induced apoptosis was essentially mediated by caspase-9. Our results therefore suggest that, in addition to the classical cytochrome c/Apaf-1-dependent pathway of caspase-9 activation, staurosporine can induce caspase-9 activation and apoptosis independently of the apoptosome. Since staurosporine derivatives have proven efficacy in clinical trials, activation of this novel pathway might represent a powerful target to induce apoptosis in multidrug-resistant tumor cells.

• Authors: Joachim Manns, Merle Daubrawa, Stefan Driessen, Florian Paasch, Nadine Hoffmann, Antje Löffler, Kirsten Lauber, Alexandra Dieterle, Sebastian Alers, Thomas Iftner, Klaus Schulze-Osthoff, Björn Stork, Sebastian Wesselborg
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 25 Issue 9 Pg. 3250-61 (Sep 2011) ISSN: 1530-6860 [Electronic] United States
• PMID: 21659556 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• APAF1 protein, human
• Antineoplastic Agents
• Apoptotic Protease-Activating Factor 1
• Proto-Oncogene Proteins c-bcl-2
• bcl-X Protein
• 7-hydroxystaurosporine
• Cytochromes c
• Caspase 9
• Staurosporine

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, physiology)
• Apoptotic Protease-Activating Factor 1 (genetics, metabolism)
• Caspase 9 (metabolism)
• Cell Line, Tumor
• Cytochromes c (genetics, metabolism)
• Gene Deletion
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Staurosporine (analogs & derivatives, pharmacology)
• bcl-X Protein (genetics, metabolism)