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Delaying mitotic exit downregulates FLIP expression and strongly sensitizes tumor cells to TRAIL

Oncogene volume 34, pages 661–669 (2015)Cite this article

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Abstract

Many of the current antitumor therapeutic strategies are based on the perturbation of the cell cycle, especially during mitosis. Antimitotic drugs trigger mitotic checkpoint activation, mitotic arrest and eventually cell death. However, mitotic slippage represents a major mechanism of resistance to these treatments. In an attempt to circumvent the process of slippage, targeting mitotic exit has been proposed as a better strategy to kill tumor cells. In this study, we show that treatments that induce mitotic checkpoint activation and mitotic arrest downregulate FLICE-like inhibitory protein (FLIP) levels and sensitize several tumor cell lines to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-induced apoptosis. Interestingly, we also demonstrate that in absence of mitotic checkpoint activation, mitotic arrest induced either by Cdc20 knockdown or overexpression of nondegradable cyclin B is sufficient to induce both FLIP downregulation and sensitivity to TRAIL. In summary, our data suggest that a combination of antimitotic drugs targeting cyclin B degradation and TRAIL might prevent mitotic slippage and allow tumor cells to reach the threshold for apoptosis induction, thereby facilitating tumor suppression.

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Acknowledgements

This work was supported by grants SAF2009-07163 and SAF2012-32824 from Ministerio de Ciencia e Innovación, Red Temática de Investigación Cooperativa en Cáncer (RTICC: RD06/0020/0068 and RD12/0036/0026), the European Community through the regional development funding program (FEDER) and Junta de Andalucía (P09-CVI-4497) to AL-R. TS-P was supported by contracts from Ministerio de Economía y Competitividad (MINECO). We are grateful to Aniek Janssen, Mónica Álvarez and Martin Vromans for providing helpful advice and discussions. We also thank FJ Fernandez-Farrán for excellent technical assistance.

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Authors and Affiliations

  1. Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas, Sevilla, Spain

    T Sánchez-Pérez & A López-Rivas

  2. Division of cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    T Sánchez-Pérez & R H Medema

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  1. T Sánchez-Pérez
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  2. R H Medema
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  3. A López-Rivas
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Correspondence to A López-Rivas.

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Sánchez-Pérez, T., Medema, R. & López-Rivas, A. Delaying mitotic exit downregulates FLIP expression and strongly sensitizes tumor cells to TRAIL. Oncogene 34, 661–669 (2015). https://doi.org/10.1038/onc.2013.601

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