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Blood, 15 November 2007, Vol. 110, No. 10, pp. 3662-3672.
Prepublished online as a Blood First Edition Paper on July 25, 2007; DOI 10.1182/blood-2007-02-073213.


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Submitted February 8, 2007
Accepted July 13, 2007

Apaf-1 and caspase-9 deficiency prevents apoptosis in a Bax-controlled pathway and promotes clonogenic survival during taxol treatment

Katja Janssen, Stephan Pohlmann, Reiner U. Janicke, Klaus Schulze-Osthoff, and Ute Fischer*

Institute of Molecular Medicine, Heinrich-Heine-University Dusseldorf, Dusseldorf, Germany

* Corresponding author; email: ute.fischer{at}uni-duesseldorf.de.

Taxane derivatives such as taxol (paclitaxel) elicit their antitumor effects at least in part by induction of apoptosis, but the underlying mechanisms are incompletely understood. Here, we employed different cellular models with deficiencies in key regulators of apoptosis to elucidate the mechanism of taxol-induced cell death. Apoptosis by taxol was reported to depend on the activation of the initiator caspase-10, however, we clearly demonstrate that taxol kills murine embryonic fibroblasts (MEFs) devoid of caspase-10 as well as human tumor cell lines deficient in caspase-10, -8 or FADD. In contrast, the lack of Apaf-1 or caspase-9, key regulators of the mitochondrial pathway, not only entirely protected against taxol-induced apoptosis but could even confer clonogenic survival, depending on the cell type and drug concentration. Thus, taxol triggers apoptosis not through caspase-10, but via caspase-9 activation at the apoptosome. This conclusion is supported by the fact that Bcl-2-overexpressing cells and Bax/Bak doubly deficient MEFs were entirely resistant to taxol-induced apoptosis. Interestingly, also the single knockout of Bim or Bax, but not that of Bak or Bid conferred partial resistance, suggesting a particular role of these mediators in the cell death pathway activated by taxol.


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