Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Resistance to anti-microtubule drug-induced cell death is determined by regulation of BimEL expression

Subjects

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

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Chan KS, Koh CG, Li HY. Mitosis-targeted anti-cancer therapies: where they stand. Cell Death Dis. 2012;3:e411.

    Article  Google Scholar 

  2. 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.

    Article  CAS  Google Scholar 

  3. 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.

    Article  Google Scholar 

  4. Orr GA, Verdier-Pinard P, McDaid H, Horwitz SB. Mechanisms of Taxol resistance related to microtubules. Oncogene. 2003;22:7280–95.

    Article  CAS  Google Scholar 

  5. Xu Z, Zhang L. BRCA1 expression serves a role in vincristine resistance in colon cancer cells. Oncol Lett. 2017;14:345–8.

    Article  CAS  Google Scholar 

  6. 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.

    Article  Google Scholar 

  7. 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.

    Article  Google Scholar 

  8. 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.

    Article  CAS  Google Scholar 

  9. 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.

    Article  CAS  Google Scholar 

  10. 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.

    Article  CAS  Google Scholar 

  11. 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.

    Article  CAS  Google Scholar 

  12. 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.

    Article  CAS  Google Scholar 

  13. 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.

    Article  CAS  Google Scholar 

  14. Manchado E, Guillamot M, Malumbres M. Killing cells by targeting mitosis. Cell Death Differ. 2012;19:369–77.

    Article  CAS  Google Scholar 

  15. 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.

    Article  CAS  Google Scholar 

  16. 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.

    Article  CAS  Google Scholar 

  17. Gascoigne KE, Taylor SS. Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell. 2008;14:111–22.

    Article  CAS  Google Scholar 

  18. 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.

    Article  CAS  Google Scholar 

  19. 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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  21. 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.

    Article  CAS  Google Scholar 

  22. 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.

    Article  CAS  Google Scholar 

  23. 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.

    Article  CAS  Google Scholar 

  24. 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.

    Article  CAS  Google Scholar 

  25. 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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  27. 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.

    Article  CAS  Google Scholar 

  28. 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.

    Article  CAS  Google Scholar 

  29. Huang S, Tang R, Randy YCP. BCL-W is a regulator of microtubule inhibitor-induced mitotic cell death. Oncotarget. 2016;7:38718–30.

    PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  31. 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

    Article  Google Scholar 

Download references

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

Authors

Corresponding author

Correspondence to Uttam Surana.

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.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-019-0727-4

This article is cited by

Search

Quick links