The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program.
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 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.
Schmidt
S
S
Institut für Biochemie und Molekularbiologie II, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
Schneider
L
L
Essmann
F
F
Cirstea
I C
IC
Kuck
F
F
Kletke
A
A
Jänicke
R U
RU
Wiek
C
C
Hanenberg
H
H
Ahmadian
M R
MR
Schulze-Osthoff
K
K
Nürnberg
B
B
Piekorz
R P
RP
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D004317:Doxorubicin / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000502:physiology*; D008870:Microtubules / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D008869:Microtubule-Associated Proteins; C120551:TACC3 protein, human; D004317:Doxorubicin; D048049:Extracellular Signal-Regulated MAP Kinases; D017239:Paclitaxel