Journal
ONCOTARGET
Volume 7, Issue 1, Pages 885-901Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.6432
Keywords
AZ 3146; mitotic spindle; polyploidy; regulated cell death; reversine
Categories
Funding
- French National Research Agency through the Investments for the Future program [ANR-10-INSB-04]
- Ligue Nationale contre le Cancer
- Associazione Italiana per la Ricerca sul Cancro (AIRC: Triennal Fellowship Antonietta Latronico)
- Fondation pour la Recherche Medicale (FRM)
- Associazione Italiana per la Ricerca sul Cancro
- Associazione Italiana per la Ricerca sul Cancro (AIRC: MFAG) [14641]
- Ministero Italiano della Salute [RF_GR-2011-02351355]
- Programma per i Giovani Ricercatori Rita Levi Montalcini
- Ligue contre le Cancer (equipe labelisee)
- Agence National de la Recherche (ANR) - Projets blancs
- ANR
- ERA-Net for Research on Rare Diseases
- Association pour la recherche sur le cancer (ARC)
- Canceropole Ile-de-France
- Institut National du Cancer (INCa)
- Institut Universitaire de France
- European Commission (ArtForce)
- European Research Council (ERC)
- LabEx Immuno-Oncology
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- SIRIC Cancer Research and Personalized Medicine (CARPEM)
- Paris Alliance of Cancer Research Institutes (PACRI)
- INSERM (French Medical Health and Research Institute)
- ANR grant from the French Research Ministry
- Fondation de France
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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 timelapse 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.
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