1. ¹Institut für Biochemie und Molekularbiologie II, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany
2. ²Institut für Molekulare Medizin, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany
3. ³Klinik für Kinder-Onkologie, -Hämatologie und -Klinische Immunologie, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany
4. ⁴Department of Pediatrics, Wells Center and Pediatric Research, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA

Correspondence: Dr RP Piekorz, Institut für Biochemie und Molekularbiologie II, Universitätsklinikum der Heinrich-Heine-Universität, D-40225 Düsseldorf, Germany. E-mail: roland.piekorz@uni-duesseldorf.de

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

Received 17 April 2007; Revised 21 May 2007; Accepted 23 May 2007; Published online 25 June 2007.

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–p21^WAF 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 p21^WAF 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 p21^WAF-associated protection of transformed cells against paclitaxel-induced cell death.