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: Mohamed Jemaà, Gwenola Manic, Gwendaline Lledo, Delphine Lissa, Christelle Reynes, Nathalie Morin, Frédéric Chibon, Antonella Sistigu, Maria Castedo, Ilio Vitale, Guido Kroemer, Ariane Abrieu
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 1 Pg. 885-901 (Jan 05 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26637805 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• Morpholines
• Protein Kinase Inhibitors
• Purines
• Tubulin Modulators
• Protein-Tyrosine Kinases
• Protein Serine-Threonine Kinases
• TTK protein, human
• Paclitaxel
• Nocodazole
• 2-(4-morpholinoanilino)-6-cyclohexylaminopurine

Topics

• Apoptosis (drug effects, genetics)
• Cell Cycle Proteins (antagonists & inhibitors, genetics, metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects, genetics)
• Diploidy
• HCT116 Cells
• Humans
• Immunoblotting
• M Phase Cell Cycle Checkpoints (drug effects, genetics)
• Microscopy, Fluorescence
• Mitosis (drug effects, genetics)
• Morpholines (pharmacology)
• Neoplasms (genetics, metabolism, pathology)
• Nocodazole (pharmacology)
• Paclitaxel (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
• Protein-Tyrosine Kinases (antagonists & inhibitors, genetics, metabolism)
• Purines (pharmacology)
• RNA Interference
• Tetraploidy
• Time-Lapse Imaging (methods)
• Tubulin Modulators (pharmacology)