title: 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.affiliation: Department of Internal Medicine I, Institute for Medical Virology and Epidemiology of Viral Diseases, University of Tübingen, Tübingen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Manns
authors.forename: Merle
authors.initials: M
authors.lastname: Daubrawa
authors.forename: Stefan
authors.initials: S
authors.lastname: Driessen
authors.forename: Florian
authors.initials: F
authors.lastname: Paasch
authors.forename: Nadine
authors.initials: N
authors.lastname: Hoffmann
authors.forename: Antje
authors.initials: A
authors.lastname: Löffler
authors.forename: Kirsten
authors.initials: K
authors.lastname: Lauber
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dieterle
authors.forename: Sebastian
authors.initials: S
authors.lastname: Alers
authors.forename: Thomas
authors.initials: T
authors.lastname: Iftner
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.forename: Björn
authors.initials: B
authors.lastname: Stork
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wesselborg
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053477:Apoptotic Protease-Activating Factor 1 / Q000235:genetics / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism*; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C506592:APAF1 protein, human; D000970:Antineoplastic Agents; D053477:Apoptotic Protease-Activating Factor 1; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C054852:7-hydroxystaurosporine; D045304:Cytochromes c; D053453:Caspase 9; D019311:Staurosporine