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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References
Ben-Porath I, Weinberg RA . (2005). The signals and pathways activating cellular senescence. Int J Biochem Cell Biol 37: 961–976.
Blagosklonny MV . (2006a). Cell senescence: hypertrophic arrest beyond the restriction point. J Cell Physiol 209: 592–597.
Blagosklonny MV . (2006b). Prolonged mitosis versus tetraploid checkpoint: how p53 measures the duration of mitosis. Cell Cycle 5: 971–975.
Blagosklonny MV, Demidenko ZN, Giovino M, Szynal C, Donskoy E, Herrmann RA et al. (2006). Cytostatic activity of paclitaxel in coronary artery smooth muscle cells is mediated through transient mitotic arrest followed by permanent post-mitotic arrest: comparison with cancer cells. Cell Cycle 5: 1574–1579.
Brito DA, Rieder CL . (2006). Mitotic checkpoint slippage in humans occurs via cyclin B destruction in the presence of an active checkpoint. Curr Biol 16: 1194–1200.
Broude EV, Swift ME, Vivo C, Chang BD, Davis BM, Kalurupalle S et al. (2007). p21(Waf1/Cip1/Sdi1) mediates retinoblastoma protein degradation. Oncogene 26: 6954–6958.
Cagnol S, Chambard JC . (2009). ERK and cell death: mechanisms of ERK-induced cell death--apoptosis, autophagy and senescence. Febs J 277: 2–21.
Campisi J, d'Adda di Fagagna F . (2007). Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8: 729–740.
Cassimeris L, Morabito J . (2004). TOGp, the human homolog of XMAP215/Dis1, is required for centrosome integrity, spindle pole organization, and bipolar spindle assembly. Mol Biol Cell 15: 1580–1590.
Collado M, Serrano M . (2006). The power and the promise of oncogene-induced senescence markers. Nat Rev Cancer 6: 472–476.
Czernick M, Rieger A, Goping IS . (2009). Bim is reversibly phosphorylated but plays a limited role in paclitaxel cytotoxicity of breast cancer cell lines. Biochem Biophys Res Commun 379: 145–150.
Demidenko ZN, Kalurupalle S, Hanko C, Lim CU, Broude E, Blagosklonny MV . (2008). Mechanism of G1-like arrest by low concentrations of paclitaxel: next cell cycle p53-dependent arrest with sub G1 DNA content mediated by prolonged mitosis. Oncogene 27: 4402–4410.
Essmann F, Engels IH, Totzke G, Schulze-Osthoff K, Janicke RU . (2004). Apoptosis resistance of MCF-7 breast carcinoma cells to ionizing radiation is independent of p53 and cell cycle control but caused by the lack of caspase-3 and a caffeine-inhibitable event. Cancer Res 64: 7065–7072.
Gascoigne KE, Taylor SS . (2008). Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell 14: 111–122.
Gaumont-Leclerc MF, Mukhopadhyay UK, Goumard S, Ferbeyre G . (2004). PEA-15 is inhibited by adenovirus E1A and plays a role in ERK nuclear export and Ras-induced senescence. J Biol Chem 279: 46802–46809.
Gergely F . (2002). Centrosomal TACCtics. Bioessays 24: 915–925.
Gergely F, Draviam VM, Raff JW . (2003). The ch-TOG/XMAP215 protein is essential for spindle pole organization in human somatic cells. Genes Dev 17: 336–341.
Gire V, Wynford-Thomas D . (1998). Reinitiation of DNA synthesis and cell division in senescent human fibroblasts by microinjection of anti-p53 antibodies. Mol Cell Biol 18: 1611–1621.
Horgan AM, Stork PJS . (2003). Examining the mechanism of Erk nuclear translocation using green fluorescent protein. Experimental Cell Research 285: 208–220.
Huck JJ, Zhang M, McDonald A, Bowman D, Hoar KM, Stringer B et al. (2010). MLN8054, an inhibitor of Aurora A kinase, induces senescence in human tumor cells both in vitro and in vivo. Mol Cancer Res 8: 373–384.
Jänicke RU, Sprengart ML, Wati MR, Porter AG . (1998). Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem 273: 9357–9360.
Janssen K, Pohlmann S, Janicke RU, Schulze-Osthoff K, Fischer U . (2007). Apaf-1 and caspase-9 deficiency prevents apoptosis in a Bax-controlled pathway and promotes clonogenic survival during paclitaxel treatment. Blood 110: 3662–3672.
Jung CK, Jung JH, Park GS, Lee A, Kang CS, Lee KY . (2006). Expression of transforming acidic coiled-coil containing protein 3 is a novel independent prognostic marker in non-small cell lung cancer. Pathol Int 56: 503–509.
Kadura S, Sazer S . (2005). SAC-ing mitotic errors: how the spindle assembly checkpoint (SAC) plays defense against chromosome mis-segregation. Cell Motil Cytoskeleton 61: 145–160.
Khodjakov A, Rieder CL . (2009). The nature of cell-cycle checkpoints: facts and fallacies. J Biol 8: 88.
Kiemeney LA, Sulem P, Besenbacher S, Vermeulen SH, Sigurdsson A, Thorleifsson G et al. (2010). A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer. Nat Genet 42: 415–419.
Kim WY, Sharpless NE . (2006). The regulation of INK4/ARF in cancer and aging. Cell 127: 265–275.
Kortlever RM, Higgins PJ, Bernards R . (2006). Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence. Nat Cell Biol 8: 877–884.
Kunitoku N, Sasayama T, Marumoto T, Zhang D, Honda S, Kobayashi O et al. (2003). CENP-A phosphorylation by Aurora-A in prophase is required for enrichment of Aurora-B at inner centromeres and for kinetochore function. Dev Cell 5: 853–864.
Lauffart B, Vaughan MM, Eddy R, Chervinsky D, DiCioccio RA, Black JD et al. (2005). Aberrations of TACC1 and TACC3 are associated with ovarian cancer. BMC Womens Health 5: 8.
LeRoy PJ, Hunter JJ, Hoar KM, Burke KE, Shinde V, Ruan J et al. (2007). Localization of human TACC3 to mitotic spindles is mediated by phosphorylation on Ser558 by Aurora A: a novel pharmacodynamic method for measuring Aurora A activity. Cancer Res 67: 5362–5370.
Ley R, Ewings KE, Hadfield K, Cook SJ . (2005). Regulatory phosphorylation of Bim: sorting out the ERK from the JNK. Cell Death Differ 12: 1008–1014.
Li Z, Zhang J, Liu Z, Woo CW, Thiele CJ . (2007). Downregulation of Bim by brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from paclitaxel but not etoposide or cisplatin-induced cell death. Cell Death Differ 14: 318–326.
Liang Y, Yan C, Schor NF . (2001). Apoptosis in the absence of caspase 3. Oncogene 20: 6570–6578.
Maehara K, Takahashi K, Saitoh S . (2010). CENP-A reduction induces a p53-dependent cellular senescence response to protect cells from executing defective mitoses. Mol Cell Biol 30: 2090–2104.
Mikule K, Delaval B, Kaldis P, Jurcyzk A, Hergert P, Doxsey S . (2007). Loss of centrosome integrity induces p38-p53-p21-dependent G1-S arrest. Nat Cell Biol 9: 160–170.
Mollinedo F, Gajate C . (2003). Microtubules, microtubule-interfering agents and apoptosis. Apoptosis 8: 413–450.
Pajalunga D, Mazzola A, Salzano AM, Biferi MG, De Luca G, Crescenzi M . (2007). Critical requirement for cell cycle inhibitors in sustaining nonproliferative states. J Cell Biol 176: 807–818.
Piekorz RP, Hoffmeyer A, Duntsch CD, McKay C, Nakajima H, Sexl V et al. (2002). The centrosomal protein TACC3 is essential for hematopoietic stem cell function and genetically interfaces with p53-regulated apoptosis. Embo J 21: 653–664.
Prencipe M, Fitzpatrick P, Gorman S, Tosetto M, Klinger R, Furlong F et al. (2009). Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro. Br J Cancer 101: 1900–1908.
Roninson IB, Broude EV, Chang BD . (2001). If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells. Drug Resist Updat 4: 303–313.
Sage J, Miller AL, Perez-Mancera PA, Wysocki JM, Jacks T . (2003). Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature 424: 223–228.
Schneider L, Essmann F, Kletke A, Rio P, Hanenberg H, Schulze-Osthoff K et al. (2008). TACC3 depletion sensitizes to paclitaxel-induced cell death and overrides p21(WAF)-mediated cell cycle arrest. Oncogene 27: 116–125.
Schneider L, Essmann F, Kletke A, Rio P, Hanenberg H, Wetzel W et al. (2007). The transforming acidic coiled coil 3 protein is essential for spindle-dependent chromosome alignment and mitotic survival. J Biol Chem 282: 29273–29283.
Schuendeln MM, Piekorz RP, Wichmann C, Lee Y, McKinnon PJ, Boyd K et al. (2004). The centrosomal, putative tumor suppressor protein TACC2 is dispensable for normal development, and deficiency does not lead to cancer. Mol Cell Biol 24: 6403–6409.
Shi J, Orth JD, Mitchison T . (2008). Cell type variation in responses to antimitotic drugs that target microtubules and kinesin-5. Cancer Res 68: 3269–3276.
Simstein R, Burow M, Parker A, Weldon C, Beckman B . (2003). Apoptosis, chemoresistance, and breast cancer: insights from the MCF-7 cell model system. Exp Biol Med (Maywood) 228: 995–1003.
Srsen V, Gnadt N, Dammermann A, Merdes A . (2006). Inhibition of centrosome protein assembly leads to p53-dependent exit from the cell cycle. J Cell Biol 174: 625–630.
Tierno MB, Kitchens CA, Petrik B, Graham TH, Wipf P, Xu FL et al. (2009). Microtubule binding and disruption and induction of premature senescence by disorazole C(1). J Pharmacol Exp Ther 328: 715–722.
Torii S, Yamamoto T, Tsuchiya Y, Nishida E . (2006). ERK MAP kinase in G cell cycle progression and cancer. Cancer Sci 97: 697–702.
Tresini M, Lorenzini A, Torres C, Cristofalo VJ . (2007). Modulation of replicative senescence of diploid human cells by nuclear ERK signaling. J Biol Chem 282: 4136–4151.
Yao R, Natsume Y, Noda T . (2007). TACC3 is required for the proper mitosis of sclerotome mesenchymal cells during formation of the axial skeleton. Cancer Sci 98: 555–562.
Yu J, Zhang L . (2005). The transcriptional targets of p53 in apoptosis control. Biochem Biophys Res Commun 331: 851–858.
Zhang R, Liu ST, Chen W, Bonner M, Pehrson J, Yen TJ et al. (2007). HP1 proteins are essential for a dynamic nuclear response that rescues the function of perturbed heterochromatin in primary human cells. Mol Cell Biol 27: 949–962.
Zyss D, Gergely F . (2009). Centrosome function in cancer: guilty or innocent? Trends Cell Biol 19: 334–346.
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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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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DOI: https://doi.org/10.1038/onc.2010.354
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