Abstract
Anti-microtubule agents are frequently used as anticancer therapeutics. Cell death induced by these agents is considered to be due to sustained mitotic arrest caused by the activation of spindle assembly checkpoint (SAC). However, some cell types are resistant to mitotic cell death. Cells’ ability to escape mitotic arrest (mitotic slippage) is thought to be a major mechanism contributing to this resistance. Here, we show that resistance to cell death induced by anti-mitotic agents is not linked to cells’ capacity to undergo mitotic slippage as generally believed but is dependent on the state of BimEL regulation during mitosis. While transcriptional repression of BimEL in the mitotic death-resistant cells involves polycomb repressive complex 2 (PRC2)-mediated histone trimethylation, the BimEL protein is destabilized by cullin 1/4A-βTrCP-dependent degradation involving activation of cullin 1/4A by neddylation. These results imply that pharmacological augmentation of BimEL activity in anti-microtubule drug-resistant tumors may have important therapeutic implications.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
Purchase on Springer Link
Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Chan KS, Koh CG, Li HY. Mitosis-targeted anti-cancer therapies: where they stand. Cell Death Dis. 2012;3:e411.
Vitale I, Galluzzi L, Castedo M, Kroemer G. Mitotic catastrophe: a mechanism for avoiding genomic instability. Nat Rev Mol Cell Biol. 2011;12:385–92.
Chumduri C, Gillissen B, Richter A, Richter A, Milojkovic A, Overkamp T, et al. Apoptosis resistance, mitotic catastrophe, and loss of ploidy control in Burkitt lymphoma. J Mol Med. 2015;93:559–72.
Orr GA, Verdier-Pinard P, McDaid H, Horwitz SB. Mechanisms of Taxol resistance related to microtubules. Oncogene. 2003;22:7280–95.
Xu Z, Zhang L. BRCA1 expression serves a role in vincristine resistance in colon cancer cells. Oncol Lett. 2017;14:345–8.
Cheung CHA, Wu S-Y, Lee T-R, Chang C-Y, Wu J-S, Hsieh H-P, et al. Cancer cells acquire mitotic drug resistance properties through beta I-tubulin mutations and alterations in the expression of beta-tubulin isotypes. PLoS ONE 2010;5:e12564.
Gonçalves A, Braguer D, Kamath K, Martello L, Briand C, Horwitz S, et al. Resistance to Taxol in lung cancer cells associated with increased microtubule dynamics. Proc Natl Acad Sci. 2001;98:11737–42.
Kutuk O, Letai A. Displacement of Bim by Bmf and Puma rather than increase in Bim level mediates paclitaxel-induced apoptosis in breast cancer cells. Cell Death Differ. 2010;17:1624–35.
Li R, Moudgil T, Ross HJ, Hu HM. Apoptosis of non-small-cell lung cancer cell lines after paclitaxel treatment involves the BH3-only proapoptotic protein Bim. Cell Death Differ. 2005;12:292–303.
Wu N, Huang Y, Zou Z, Gimenez-Capitan A, Yu L, Hu W, et al. High BIM mRNA levels are associated with longer survival in advanced gastric cancer. Oncol Lett. 2017;13:1826–34.
Yamaguchi H, Chen J, Bhalla K, Wang H-G. Regulation of Bax activation and apoptotic response to microtubule-damaging agents by p53 transcription-dependent and -independent pathways. J Biol Chem. 2004;279:39431–7.
Haschka MD, Soratroi C, Kirschnek S, Häcker G, Hilbe R, Geley S, et al. The NOXA–MCL1–BIM axis defines lifespan on extended mitotic arrest. Nat Commun. 2015;6:6891.
Wan L, Tan M, Yang J, Inuzuka H, Dai X, Wu T, et al. APC(Cdc20) suppresses apoptosis through targeting Bim for ubiquitination and destruction. Dev Cell. 2014;29:377–91.
Manchado E, Guillamot M, Malumbres M. Killing cells by targeting mitosis. Cell Death Differ. 2012;19:369–77.
Sinnott R, Winters L, Larson B, Mytsa D, Taus P, Cappell KM, et al. Mechanisms promoting escape from mitotic-stress induced tumor cell death. Cancer Res. 2014;74:3857–69.
Brito DA, Rieder CL. The ability to survive mitosis in the presence of microtubule poisons differs significantly between human nontransformed (RPE-1) and cancer (U2OS, HeLa) cells. Cell Motil Cytoskelet. 2009;66:437–47.
Gascoigne KE, Taylor SS. Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell. 2008;14:111–22.
Knehr M, Poppe M, Enulescu M, Eickelbaum W, Stoehr M, Schroeter D, et al. A critical appraisal of synchronization methods applied to achieve maximal enrichment of HeLa cells in specific cell cycle phases. Exp Cell Res. 1995;217:546–53.
Harley ME, Allan LA, Sanderson HS, Clarke PR. Phosphorylation of Mcl-1 by CDK1–cyclin B1 initiates its Cdc20-dependent destruction during mitotic arrest. EMBO J. 2010;29:2407–20.
Pathan N, Aime-Sempe C, Kitada S, Basu A, Haldar S, Reed JC. Microtubule-targeting drugs induce Bcl-2 phosphorylation and association with Pin1. Neoplasia. 2001;3:550–9.
Terrano DT, Upreti M, Chambers TC. Cyclin-dependent kinase 1-mediated Bcl-x(L)/Bcl-2 phosphorylation acts as a functional link coupling mitotic arrest and apoptosis. Mol Cell Biol. 2010;30:640–56.
Jiang L, Rong R, Sheikh MS, Huang Y. Cullin-4A·DNA damage-binding protein 1 E3 ligase complex targets tumor suppressor RASSF1A for degradation during mitosis. J Biol Chem. 2011;286:6971–8.
Balachandran RS, Heighington CS, Starostina NG, Anderson JW, Owen DL, Vasudevan S, et al. The ubiquitin ligase CRL2(ZYG11) targets cyclin B1 for degradation in a conserved pathway that facilitates mitotic slippage. J Cell Biol. 2016;215:151–66.
Thomas Y, Coux O, Baldin V. βTrCP-dependent degradation of CDC25B phosphatase at the metaphase-anaphase transition is a pre-requisite for correct mitotic exit. Cell Cycle. 2010;9:4338–50.
Zhang W, Cheng GZ, Gong J, Hermanto U, Zong CS, Chan J, et al. RACK1 and CIS mediate the degradation of BimEL in cancer cells. J Biol Chem. 2008;283:16416–26.
Dehan E, Bassermann F, Guardavaccaro D, Vasiliver-Shamis G, Cohen M, Lowes K, et al. βTrCP- and Rsk1/2-mediated degradation of BimEL inhibits apoptosis. Mol Cell. 2009;33:109–16.
Ridinger-Saison M, Evanno E, Gallais I, Rimmelé P, Selimoglu-Buet D, Sapharikas E, et al. Epigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia. Cell Death Differ. 2013;20:1268–78.
Bah N, Maillet L, Ryan J, Dubreil S, Gautier F, Letai A, et al. Bcl-xL controls a switch between cell death modes during mitotic arrest. Cell Death & Dis. 2014;5:e1291.
Huang S, Tang R, Randy YCP. BCL-W is a regulator of microtubule inhibitor-induced mitotic cell death. Oncotarget. 2016;7:38718–30.
Rieder CL, Maiato H. Stuck in division or passing through: what happens when cells cannot satisfy the spindle assembly checkpoint. Dev Cell. 2004;7:637–51.
He Y, Yan D, Zheng D, Hu Z, Li H, Li J. Cell division cycle 6 promotes mitotic slippage and contributes to drug resistance in paclitaxel-treated cancer cells. PLoS ONE 2016;11:e0162633
Acknowledgements
We thank the members of the US laboratory for helpful discussions and the mouse model unit (IMCB, Singapore) for kindly providing the PLKO.1 vector and lentiviral packaging vectors. The U.S. lab is supported by the Biomedical Research Council of A*STAR (Agency for Science, Technology and Research), Singapore.
Author contributions
WR, GV and US conceived and designed the experiments. WR and GV performed the experiments. RMS, LC, LCW, AJ and KP assisted in some of the experiments. WR, GV and US analyzed the data. WR, GV and US wrote the paper.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Ruan, W., Venkatachalam, G., Sobota, R.M. et al. Resistance to anti-microtubule drug-induced cell death is determined by regulation of BimEL expression. Oncogene 38, 4352–4365 (2019). https://doi.org/10.1038/s41388-019-0727-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41388-019-0727-4
This article is cited by
-
Constitutive BAK/MCL1 complexes predict paclitaxel and S63845 sensitivity of ovarian cancer
Cell Death & Disease (2021)