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The chemotherapeutic agent paclitaxel inhibits autophagy through two distinct mechanisms that regulate apoptosis

Oncogene volume 32, pages 736–746 (2013)Cite this article

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Abstract

Anti-mitotic agents such as paclitaxel and docetaxel are widely used for the treatment of breast, ovarian and lung cancers. Although paclitaxel induces apoptosis, this drug also modulates autophagy. How autophagy affects paclitaxel activity, is unclear. We discovered that paclitaxel inhibited autophagy through two distinct mechanisms dependent on cell cycle stage. In mitotic cells, paclitaxel blocked activation of the class III phosphatidyl inositol 3 kinase, Vps34, a critical initiator of autophagosome formation. In non-mitotic paclitaxel-treated cells, autophagosomes were generated but their movement and maturation was inhibited. Chemically or genetically blocking autophagosome formation diminished paclitaxel-induced cell death suggesting that autophagosome accumulation sensitized cells to paclitaxel toxicity. In line with these observations, we identified that primary breast tumors that expressed diminished levels of autophagy-initiating genes were resistant to taxane therapy, identifying possible mechanisms and prognostic markers of clinical chemotherapeutic resistance.

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Acknowledgements

This work was supported by operating grants from the Canadian Breast Cancer Foundation and Alberta Cancer Foundation/Alberta Innovates-Health Solutions (project #25011) awarded to ISG. We thank Dr Junying Yuan for the kind gift of the anti-phospho T159 Vps34 antibody. We thank the Goping lab, Simmen lab and Signal Transduction Research Group for valuable discussions. Owing to journal reference restraints, we apologize to those investigators whose work was not cited.

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Authors and Affiliations

  1. Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada

    R A Veldhoen, S L Banman, R Odsen & I S Goping

  2. Department of Biology and Environmental Science, Concordia University College, Edmonton, Alberta, Canada

    D R Hemmerling

  3. Department of Cell Biology, University of Alberta, Edmonton, Alberta, Canada

    T Simmen & A J Simmonds

  4. Department of Oncology, University of Alberta, Edmonton, Alberta, Canada

    D A Underhill & I S Goping

Authors
  1. R A Veldhoen
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  2. S L Banman
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Correspondence to I S Goping.

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Veldhoen, R., Banman, S., Hemmerling, D. et al. The chemotherapeutic agent paclitaxel inhibits autophagy through two distinct mechanisms that regulate apoptosis. Oncogene 32, 736–746 (2013). https://doi.org/10.1038/onc.2012.92

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  • DOI: https://doi.org/10.1038/onc.2012.92

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