Paclitaxel promotes a caspase 8-mediated apoptosis through death effector domain association with microtubules

Oncogene. 2009 Oct 8;28(40):3551-62. doi: 10.1038/onc.2009.210. Epub 2009 Aug 10.


Microtubule-perturbing drugs have become front-line chemotherapeutics, inducing cell-cycle crisis as a major mechanism of action. However, these agents show pleiotropic effects on cells and can induce apoptosis through other means. Paclitaxel, a microtubule-stabilizing agent, induces a caspase-dependent apoptosis, although the precise mechanism(s) remain unclear. Here, we used genetic approaches to evaluate the role of caspase 8 in paclitaxel-mediated apoptosis. We observed that caspase 8-expressing cells are more sensitive to paclitaxel than caspase 8-deficient cells. Mechanistically, caspase 8 was found associated with microtubules, and this interaction increased after paclitaxel treatment. The prodomains death effector domains (DEDs) of caspase 8 were sufficient for interaction with microtubules, but the caspase 8 holoprotein was required for apoptosis. DED-only forms of caspase 8 were found in both primary and tumor cell lines, associating with perinuclear microtubules and the centrosome. Microtubule association, and paclitaxel sensitivity, depends on a critical lysine (K156) within a microtubule-binding motif (KLD) in DED-b of caspase 8. The results show an unexpected pathway of apoptosis mediated by caspase 8.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects*
  • Caspase 8 / chemistry
  • Caspase 8 / physiology*
  • Cell Line, Tumor
  • Centrosome / physiology
  • Humans
  • Microtubules / physiology*
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / pathology
  • Paclitaxel / pharmacology*
  • Protein Structure, Tertiary


  • Antineoplastic Agents, Phytogenic
  • Caspase 8
  • Paclitaxel