TACC3 depletion sensitizes to paclitaxel-induced cell death and overrides p21WAF-mediated cell cycle arrest.
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.
Schneider
L
L
Institut für Biochemie und Molekularbiologie II, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
Essmann
F
F
Kletke
A
A
Rio
P
P
Hanenberg
H
H
Schulze-Osthoff
K
K
Nürnberg
B
B
Piekorz
R P
RP
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D002453:Cell Cycle / Q000235:genetics*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics; D005326:Fetal Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins; D041681:NIH 3T3 Cells; D017239:Paclitaxel / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D000972:Antineoplastic Agents, Phytogenic; D002352:Carrier Proteins; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005326:Fetal Proteins; D008869:Microtubule-Associated Proteins; C418485:TACC3 protein, mouse; D016159:Tumor Suppressor Protein p53; D017239:Paclitaxel