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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. This Article Full Text Full Text (PDF) Supplemental Methods and Figure All Versions of this Article: blood-2007-02-073213v1 110/10/3662    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Janssen, K. Articles by Fischer, U. Search for Related Content PubMed PubMed Citation Articles by Janssen, K. Articles by Fischer, U. Related Collections Immunobiology Apoptosis Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Apaf-1 and caspase-9 deficiency prevents apoptosis in a Bax-controlled pathway and promotes clonogenic survival during paclitaxel treatment Katja Janssen1, Stephan Pohlmann1, Reiner U. Jänicke1, Klaus Schulze-Osthoff1, and Ute Fischer1 1 Institute of Molecular Medicine, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany Taxane derivatives such as paclitaxel elicit their antitumor effects at least in part by induction of apoptosis, but the underlying mechanisms are incompletely understood. Here, we used different cellular models with deficiencies in key regulators of apoptosis to elucidate the mechanism of paclitaxel-induced cell death. Apoptosis by paclitaxel was reported to depend on the activation of the initiator caspase-10; however, we clearly demonstrate that paclitaxel kills murine embryonic fibroblasts (MEFs) devoid of caspase-10 as well as human tumor cell lines deficient in caspase-10, caspase-8, or Fas-associating protein with death domain. In contrast, the lack of Apaf-1 or caspase-9, key regulators of the mitochondrial pathway, not only entirely protected against paclitaxel-induced apoptosis but could even confer clonogenic survival, depending on the cell type and drug concentration. Thus, paclitaxel 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 paclitaxel-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 paclitaxel. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Taxol therapy revisited Shida Yousefi and Hans-Uwe Simon Blood 2007 110: 3492. [Full Text] [PDF]

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