Inhibition of Chk1 kills tetraploid tumor cells through a p53-dependent pathway

Ilio Vitale, Lorenzo Galluzzi, Sonia Vivet, Lisa Nanty, Philippe Dessen, Laura Senovilla, Ken A. Olaussen, Vladimir Lazar, Michelle Prudhomme, Roy M. Golsteyn, Maria Castedo, Guido Kroemer

Research output: Contribution to journalArticle

Abstract

Tetraploidy constitutes an adaptation to stress and an intermediate step between euploidy and aneuploidy in oncogenesis. Tetraploid cells are particularly resistant against genotoxic stress including radiotherapy and chemotherapy. Here, we designed a strategy to preferentially kill tetraploid tumor cells. Depletion of checkpoint kinase-1 (Chk1) by siRNAs, transfection with dominant-negative Chk1 mutants or pharmacological Chk1 inhibition killed tetraploid colon cancer cells yet had minor effects on their diploid counterparts. Chk1 inhibition abolished the spindle assembly checkpoint and caused premature and abnormal mitoses that led to p53 activation and cell death at a higher frequency in tetraploid than in diploid cells. Similarly, abolition of the spindle checkpoint by knockdown of Bub1, BubR1 or Mad2 induced P53-dependent apoptosis of tetraploid cells. Chk1 inhibition reversed the cisplatin resistance of tetraploid cells in vitro and in vivo, in xenografted human cancers. Chk1 inhibition activated p53-regulated transcripts including Puma/BBC3 in tetraploid but not in diploid tumor cells. Altogether, our results demonstrate that, in tetraploid tumor cells, the inhibition of Chk1 sequentially triggers aberrant mitosis, p53 activation and Puma/BBC3-dependent mitochondrial apoptosis.

Original languageEnglish
Article numbere1337
JournalPLoS One
Volume2
Issue number12
DOIs
Publication statusPublished - Dec 26 2007

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Vitale, I., Galluzzi, L., Vivet, S., Nanty, L., Dessen, P., Senovilla, L., Olaussen, K. A., Lazar, V., Prudhomme, M., Golsteyn, R. M., Castedo, M., & Kroemer, G. (2007). Inhibition of Chk1 kills tetraploid tumor cells through a p53-dependent pathway. PLoS One, 2(12), [e1337]. https://doi.org/10.1371/journal.pone.0001337