title: Whole-genome duplication increases tumor cell sensitivity to MPS1 inhibition.
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.
authors.affiliation: CRBM, CNRS UMR5237, Université de Montpellier, Montpellier, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Jemaà
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Gwenola
authors.initials: G
authors.lastname: Manic
authors.affiliation: CRBM, CNRS UMR5237, Université de Montpellier, Montpellier, France.
authors.forename: Gwendaline
authors.initials: G
authors.lastname: Lledo
authors.affiliation: Université Paris-Sud/Paris XI, Le Kremlin-Bicêtre, France.|INSERM, UMRS1138, Paris, France.|Equipe 11 Labelisée par la Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.|Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Lissa
authors.affiliation: EA 2415, Laboratoire de Biostatistique, d'Epidémiologie et de Recherche Clinique, Université de Montpellier, Montpellier, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Reynes
authors.affiliation: CRBM, CNRS UMR5237, Université de Montpellier, Montpellier, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Morin
authors.affiliation: Department of Biopathology, Institut Bergonié, Comprehensive Cancer Centre, Bordeaux, France.|INSERM U916, Bordeaux, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Chibon
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Sistigu
authors.affiliation: Université Paris-Sud/Paris XI, Le Kremlin-Bicêtre, France.|INSERM, UMRS1138, Paris, France.|Equipe 11 Labelisée par la Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.|Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Castedo
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy.|Department of Biology, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Ilio
authors.initials: I
authors.lastname: Vitale
authors.affiliation: INSERM, UMRS1138, Paris, France.|Equipe 11 Labelisée par la Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.|Université Pierre et Marie Curie/Paris VI, Paris, France.|Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.|Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: CRBM, CNRS UMR5237, Université de Montpellier, Montpellier, France.
authors.forename: Ariane
authors.initials: A
authors.lastname: Abrieu
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004171:Diploidy; D045325:HCT116 Cells; D006801:Humans; D015151:Immunoblotting; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D008856:Microscopy, Fluorescence; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D009025:Morpholines / Q000494:pharmacology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015739:Nocodazole / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology; D034622:RNA Interference; D057891:Tetraploidy; D059008:Time-Lapse Imaging / Q000379:methods; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: D018797:Cell Cycle Proteins; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011687:Purines; D050257:Tubulin Modulators; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human; D017239:Paclitaxel; D015739:Nocodazole; C484369:2-(4-morpholinoanilino)-6-cyclohexylaminopurine
keywords: AZ 3146; mitotic spindle; polyploidy; regulated cell death; reversine