title: Inhibition of Chk1 kills tetraploid tumor cells through a p53-dependent pathway.
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.
authors.affiliation: INSERM, U848, Cancer and Immunity, Villejuif, France.
authors.forename: Ilio
authors.initials: I
authors.lastname: Vitale
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Galluzzi
authors.forename: Sonia
authors.initials: S
authors.lastname: Vivet
authors.forename: Lisa
authors.initials: L
authors.lastname: Nanty
authors.forename: Philippe
authors.initials: P
authors.lastname: Dessen
authors.forename: Laura
authors.initials: L
authors.lastname: Senovilla
authors.forename: Ken A
authors.initials: KA
authors.lastname: Olaussen
authors.forename: Vladimir
authors.initials: V
authors.lastname: Lazar
authors.forename: Michelle
authors.initials: M
authors.lastname: Prudhomme
authors.forename: Roy M
authors.initials: RM
authors.lastname: Golsteyn
authors.forename: Maria
authors.initials: M
authors.lastname: Castedo
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D002945:Cisplatin / Q000494:pharmacology; D006801:Humans; D011123:Polyploidy; D011494:Protein Kinases / Q000187:drug effects*; D015398:Signal Transduction; D008941:Spindle Apparatus; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D002945:Cisplatin