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

S. Schmidt, L. Schneider, F. Essmann, I. C. Cirstea, F. Kuck, A. Kletke, R. U. Jänicke, C. Wiek, H. Hanenberg, M. R. Ahmadian, K. Schulze-Osthoff, B. Nürnberg, R. P. Piekorz

Research output: Contribution to journalArticle

34 Scopus citations

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 G 1 through a cellular senescence program characterized by the upregulation of nuclear p21 WAF, 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.

Original languageEnglish (US)
Pages (from-to)6184-6192
Number of pages9
JournalOncogene
Volume29
Issue number46
DOIs
StatePublished - Nov 18 2010

Keywords

  • centrosome
  • mitosis
  • p21WAF
  • paclitaxel
  • premature senescence
  • TACC3

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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    Schmidt, S., Schneider, L., Essmann, F., Cirstea, I. C., Kuck, F., Kletke, A., Jänicke, R. U., Wiek, C., Hanenberg, H., Ahmadian, M. R., Schulze-Osthoff, K., Nürnberg, B., & Piekorz, R. P. (2010). The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program. Oncogene, 29(46), 6184-6192. https://doi.org/10.1038/onc.2010.354