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

• Published in: PloS one 2007-12, Vol.2 (12), p.e1337-e1337
• Main Authors: Vitale, Ilio, Galluzzi, Lorenzo, Vivet, Sonia, Nanty, Lisa, Dessen, Philippe, Senovilla, Laura, Olaussen, Ken A, Lazar, Vladimir, Prudhomme, Michelle, Golsteyn, Roy M, Castedo, Maria, Kroemer, Guido
• Format: Article
• Language: English
• Subjects: Aberration; Aneuploidy; Apoptosis; Apoptosis - drug effects; BUBR1 protein; Cancer; Cancer prevention; Cell activation; Cell Biology/Cell Growth and Division; Cell Biology/Cellular Death and Stress Responses; Cell cycle; Cell death; Cell division; Cell Line, Tumor; Checkpoint Kinase 1; Chemical Sciences; Chemotherapy; CHK1 protein; Cisplatin; Cisplatin - pharmacology; Colon; Colon cancer; Deoxyribonucleic acid; DNA; DNA damage; Genetics and Genomics/Cancer Genetics; Genotoxicity; Humans; Infection; Inhibition; Kinases; Medical prognosis; Mitochondria; Mitosis; Mutants; Organic chemistry; p53 Protein; Pharmacology; Phosphorylation; Polyploidy; Protein Kinases - drug effects; Radiation therapy; Signal Transduction; siRNA; Spindle Apparatus; Tetraploidy; Transfection; Tumor cells; Tumor proteins; Tumor Suppressor Protein p53 - physiology; Tumorigenesis; Tumors; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0001337

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.