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

Oncogene volume 28, pages 3551–3562 (2009)Cite this article

Abstract

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.

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Acknowledgements

This work was supported by the NIH/NCI Grant CA107263 to DGS and by grants from the Swiss National Foundation, the Novartis Foundation and the Caja Madrid Foundation to AM. The authors thank Drs S Zeitlin and M Hogan for helpful comments and Drs Marcus Peter (Ben May Institute), Jill Lahti (St Jude Children's Research Hospital), Mark Ginsberg (UCSD) and Guy Salvesen (The Burnham Institute) for the kind gift of reagents.

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Authors and Affiliations

  1. Department of Pathology, University of California San Diego School of Medicine, La Jolla, CA, USA

    A Mielgo, V A Torres, S Barbero & D G Stupack

  2. Moores Comprehensive Cancer Center, University of California San Diego School of Medicine, La Jolla, CA, USA

    A Mielgo, V A Torres, K Clair, S Barbero & D G Stupack

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  1. A Mielgo
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  2. V A Torres
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  3. K Clair
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  4. S Barbero
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Correspondence to D G Stupack.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Mielgo, A., Torres, V., Clair, K. et al. Paclitaxel promotes a caspase 8-mediated apoptosis through death effector domain association with microtubules. Oncogene 28, 3551–3562 (2009). https://doi.org/10.1038/onc.2009.210

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