Whole-genome duplication increases tumor cell sensitivity to MPS1 inhibition

Mohamed Jemaà, Gwenola Manic, Gwendaline Lledo, Delphine Lissa, Christelle Reynes, Nathalie Morin, Frédéric Chibon, Antonella Sistigu, Maria Castedo, Ilio Vitale, Guido Kroemer, Ariane Abrieu

Research output: Contribution to journalArticle

Abstract

Several lines of evidence indicate that whole-genome duplication resulting in tetraploidy facilitates carcinogenesis by providing an intermediate and metastable state more prone to generate oncogenic aneuploidy. Here, we report a novel strategy to preferentially kill tetraploid cells based on the abrogation of the spindle assembly checkpoint (SAC) via the targeting of TTK protein kinase (better known as monopolar spindle 1, MPS1). The pharmacological inhibition as well as the knockdown of MPS1 kills more efficiently tetraploid cells than their diploid counterparts. By using time-lapse videomicroscopy, we show that tetraploid cells do not survive the aborted mitosis due to SAC abrogation upon MPS1 depletion. On the contrary diploid cells are able to survive up to at least two more cell cycles upon the same treatment. This effect might reflect the enhanced difficulty of cells with whole-genome doubling to tolerate a further increase in ploidy and/or an elevated level of chromosome instability in the absence of SAC functions. We further show that MPS1-inhibited tetraploid cells promote mitotic catastrophe executed by the intrinsic pathway of apoptosis, as indicated by the loss of mitochondrial potential, the release of the pro-apoptotic cytochrome c from mitochondria, and the activation of caspases. Altogether, our results suggest that MPS1 inhibition could be used as a therapeutic strategy for targeting tetraploid cancer cells.

Original languageEnglish
Pages (from-to)885-901
Number of pages17
JournalOncotarget
Volume7
Issue number1
DOIs
Publication statusPublished - Jan 5 2016

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Keywords

  • Apoptosis
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Survival
  • Diploidy
  • HCT116 Cells
  • Humans
  • Immunoblotting
  • M Phase Cell Cycle Checkpoints
  • Microscopy, Fluorescence
  • Mitosis
  • Morpholines
  • Neoplasms
  • Nocodazole
  • Paclitaxel
  • Protein Kinase Inhibitors
  • Protein-Serine-Threonine Kinases
  • Protein-Tyrosine Kinases
  • Purines
  • RNA Interference
  • Tetraploidy
  • Time-Lapse Imaging
  • Tubulin Modulators
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Jemaà, M., Manic, G., Lledo, G., Lissa, D., Reynes, C., Morin, N., Chibon, F., Sistigu, A., Castedo, M., Vitale, I., Kroemer, G., & Abrieu, A. (2016). Whole-genome duplication increases tumor cell sensitivity to MPS1 inhibition. Oncotarget, 7(1), 885-901. https://doi.org/10.18632/oncotarget.6432