Whole-genome duplication increases tumor cell sensitivity to MPS1 inhibition

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

doi:10.18632/oncotarget.6432

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.

Highlights

Aneuploidy, the condition of having an imbalanced copy number of chromosomes (DNA content ≠ xn, where n stands for the haploid chromosome set and x ≥ 1), and chromosome instability (CIN), a type of genomic instability in which cells display an elevated rate of whole-chromosome mis-segregations (~1 per 5 cell divisions) and frequently change their karyotype [1], are widespread in human tumors [2,3,4,5]
In this study we developed a novel strategy for targeting tetraploid tumor cells based on the abrogation of the mitotic kinase monopolar spindle 1 (MPS1)
By employing different pairs of tumor clones generated from the same parental cell lines and displaying distinct levels of ploidy we provided strong evidence that the depletion or inhibition of MPS1 potently kills tetraploid cancer cells via a mechanism involving the induction of mitotic catastrophe following aberrant or aborted cell divisions, and the activation of a mitochondrion- and caspase-dependent pathway of regulated cell death

Summary

Introduction

Aneuploidy, the condition of having an imbalanced copy number of chromosomes (DNA content ≠ xn, where n stands for the haploid chromosome set and x ≥ 1), and chromosome instability (CIN), a type of genomic instability in which cells display an elevated rate of whole-chromosome mis-segregations (~1 per 5 cell divisions) and frequently change their karyotype [1], are widespread in human tumors [2,3,4,5]. According to the current hypotheses, illicitly generated tetraploids are less likely to stably maintain their karyotype across consecutive generations due to intrinsic defects in the machineries involved in DNA replication, DNA repair and/or chromosome segregation [19,20,21]. These defects might increase the level of CIN, in turn resulting in the generation of aneuploid cells [14, 19, 22]. Aneuploid cells generated from tetraploid cells often display elevated tumorigenicity [14, 16, 17, 19, 22]

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Results

Conclusion