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TACC3 depletion sensitizes to paclitaxel-induced cell death and overrides p21WAF-mediated cell cycle arrest

Oncogene volume 27, pages 116–125 (2008)Cite this article

Abstract

Regulators of the mitotic spindle apparatus are attractive cellular targets for antitumor therapy. The centrosomal protein transforming acidic coiled coil (TACC) 3 is required for spindle assembly and proper chromosome segregation. In this study, we employed an inducible RNA interference approach to downregulate TACC3 expression. We show that TACC3 knock-down in NIH3T3 fibroblasts caused aneuploidy, but failed to overtly impair mitotic progression. TACC3 depletion rather triggered a postmitotic p53–p21WAF pathway and led to a reversible cell cycle arrest. Similar effects were induced by low concentrations of paclitaxel, a spindle poison used in antitumor therapy. Interestingly, however, and unlike in TACC3-proficient cells, paclitaxel was able to induce strong polyploidy and subsequent apoptosis in TACC3-depleted cells. Even though paclitaxel treatment was associated with the activation of the survival kinase Akt and an antiapoptotic expression of cytoplasmic p21WAF and cyclin D1, this inhibition of cell death was abrogated by depletion of TACC3. Thus, our data identify TACC3 as a potential target to overcome p21WAF-associated protection of transformed cells against paclitaxel-induced cell death.

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Acknowledgements

We thank Didier Trono (Swiss Federal Institute of Technology, Laussane) and Lars-Oliver Klotz (Institut für Umweltmedizinische Forschung, Düsseldorf) for kindly providing constructs for lentivector-mediated RNA interference and antibodies, respectively. We are indebted to Antje Gohla, Reiner U Jänicke, Mohamad Ahmadian, Chris Wichmann and members of the department for critical comments on the manuscript. This work was supported by intramural grant 9772210 from the Medical Faculty of the Heinrich-Heine-University Düsseldorf (to RPP) and by the Deutsche Forschungsgemeinschaft (to HH, KSO, BN and RPP), by the Deutsche Jose Carreras Stiftung (to HH) and by Fonds der Chemischen Industrie (to KSO).

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  1. P Rio

    Present address: 5Current address: Hematopoietic Gene Therapy Program, CIEMAT, Madrid, Spain.,

Authors and Affiliations

  1. Institut für Biochemie und Molekularbiologie II, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany

    L Schneider, A Kletke, B Nürnberg & R P Piekorz

  2. Institut für Molekulare Medizin, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany

    F Essmann & K Schulze-Osthoff

  3. Klinik für Kinder-Onkologie, -Hämatologie und -Klinische Immunologie, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany

    P Rio & H Hanenberg

  4. Department of Pediatrics, Wells Center and Pediatric Research, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA

    H Hanenberg

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Correspondence to R P Piekorz.

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

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Schneider, L., Essmann, F., Kletke, A. et al. TACC3 depletion sensitizes to paclitaxel-induced cell death and overrides p21WAF-mediated cell cycle arrest. Oncogene 27, 116–125 (2008). https://doi.org/10.1038/sj.onc.1210628

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