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The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

Oncogene volume 29, pages 6184–6192 (2010)Cite this article

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Abstract

Microtubule-interfering cancer drugs such as paclitaxel (PTX) often cause chemoresistance and severe side effects, including neurotoxicity. To explore potentially novel antineoplastic molecular targets, we investigated the cellular response of breast carcinoma cells to short hairpin(sh)RNA-mediated depletion of the centrosomal protein transforming acidic coiled coil (TACC) 3, an Aurora A kinase target expressed during mitosis. Unlike PTX, knockdown of TACC3 did not trigger a cell death response, but instead resulted in a progressive loss of the pro-apoptotic Bcl-2 protein Bim that links microtubule integrity to spindle poison-induced cell death. Interestingly, TACC3-depleted cells arrested in G1 through a cellular senescence program characterized by the upregulation of nuclear p21WAF, downregulation of the retinoblastoma protein and extracellular signal-regulated kinase 1/2, formation of HP1γ (phospho-Ser83)-positive senescence-associated heterochromatic foci and increased senescence-associated β-galactosidase activity. Remarkably, the onset of senescence following TACC3 knockdown was strongly accelerated in the presence of non-toxic PTX concentrations. Thus, we conclude that mitotic spindle stress is a major trigger of premature senescence and propose that the combined targeting of the centrosomal Aurora A–TACC3 axis together with drugs interfering with microtubule dynamics may efficiently improve the chemosensitivity of cancer cells.

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Acknowledgements

We thank Didier Trono (Swiss Federal Institute of Technology, Lausanne) and Jim Ihle (St Jude Children's Research Hospital, Memphis) for kindly providing viral constructs for RNA interference and retroviral transduction. Thanks to Aliaksei Shymanets for help with densitometric evaluation and to Chris Wichmann, Veronika Sexl, Richard Moriggl, Olga Modlich, Holger Bastians, Ute Fischer, Miguel Pujana, Aris Astrinidis, and members of the department for input and critical comments. We thank the Elterninitiative Kinderkrebsklinik e.V. for a generous contribution to the confocal laser scanning microscope core facility. Grant support: Collaborative Research Centers SFB728 (RUJ, RPP), SFB773 (FE, KSO), and SPP1230 (HH) of the Deutsche Forschungsgemeinschaft; Forschungskommission (Medizinische Fakultät) of the Heinrich-Heine-Universität (ICC, MRA, RUJ, RPP); and the NGFNplus program (grant 01GS08100 to MRA) and the network for bone marrow failure syndromes (bmfs to HH) of the Bundesministerium für Bildung und Forschung.

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Author notes

  1. L Schneider

    Present address: 8Current address: IFOM Foundation—FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy.,

  2. S Schmidt and L Schneider: These authors contributed equally to this work.

Authors and Affiliations

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

    S Schmidt, L Schneider, I C Cirstea, F Kuck, A Kletke, M R Ahmadian, B Nürnberg & R P Piekorz

  2. Abteilung für Molekulare Medizin, Interfakultäres Institut für Biochemie (IFIB), Eberhard Karls Universität, Tübingen, Germany

    F Essmann & K Schulze-Osthoff

  3. Klinik für Strahlentherapie und Radioonkologie, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany

    R U Jänicke

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

    C Wiek & H Hanenberg

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

    H Hanenberg

  6. Institut für Experimentelle und Klinische Pharmakologie und Toxikologie und Interfakultäres Zentrum für Pharmakogenomik und Arzneimittelforschung (ICePhA), Klinikum der Eberhard Karls Universität, Tübingen, Germany

    B Nürnberg

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Schmidt, S., Schneider, L., Essmann, F. et al. The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program. Oncogene 29, 6184–6192 (2010). https://doi.org/10.1038/onc.2010.354

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