title: Mitotic catastrophe constitutes a special case of apoptosis whose suppression entails aneuploidy.
abstract: A conflict in cell cycle progression or DNA damage can lead to mitotic catastrophe when the DNA structure checkpoints are inactivated, for instance when the checkpoint kinase Chk2 is inhibited. Here we show that in such conditions, cells die during the metaphase of the cell cycle, as a result of caspase activation and subsequent mitochondrial damage. Molecular ordering of these phenomena reveals that mitotic catastrophe occurs in a p53-independent manner and involves a primary activation of caspase-2, upstream of cytochrome c release, followed by caspase-3 activation and chromatin condensation. Suppression of caspase-2 by RNA interference or pseudosubstrate inhibitors as well as blockade of the mitochondrial membrane permeabilization prevent the mitotic catastrophe and allow cells to further proceed the cell cycle beyond the metaphase, leading to asymmetric cell division. Heterokarya generated by the fusion of nonsynchronized cells can be driven to divide into three or more daughter cells when Chk2 and caspases are simultaneously inhibited. Such multipolar divisions, resulting from suppressed mitotic catastrophe, lead to the asymmetric distribution of cytoplasm (anisocytosis), DNA (anisokaryosis) and chromosomes (aneuploidy). Similarly, in a model of DNA damage-induced mitotic catastrophe, suppression of apoptosis leads to the generation of aneuploid cells. Our findings delineate a molecular pathway through which DNA damage, failure to arrest the cell cycle and inhibition of apoptosis can favor the occurrence of cytogenetic abnormalities that are likely to participate in oncogenesis.
authors.affiliation: CNRS-UMR 8125, Institut Gustave Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Castedo
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Perfettini
authors.forename: Thomas
authors.initials: T
authors.lastname: Roumier
authors.forename: Alexander
authors.initials: A
authors.lastname: Valent
authors.forename: Hana
authors.initials: H
authors.lastname: Raslova
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yakushijin
authors.forename: David
authors.initials: D
authors.lastname: Horne
authors.forename: Jean
authors.initials: J
authors.lastname: Feunteun
authors.forename: Gilbert
authors.initials: G
authors.lastname: Lenoir
authors.forename: René
authors.initials: R
authors.lastname: Medema
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000782:Aneuploidy; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001381:Azepines / Q000494:pharmacology; D015704:CD4 Antigens / Q000235:genetics; D053143:Caspase 2; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology*; D002455:Cell Division; D002459:Cell Fusion; D045744:Cell Line, Tumor / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D018385:Centrosome / Q000502:physiology / Q000648:ultrastructure; D064447:Checkpoint Kinase 2; D003110:Colonic Neoplasms / Q000473:pathology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D015752:Genes, env; D015726:Giant Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006367:HeLa Cells / Q000166:cytology / Q000201:enzymology; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D008677:Metaphase; D008928:Mitochondria / Q000502:physiology / Q000648:ultrastructure; D008938:Mitosis / Q000235:genetics; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology; D034622:RNA Interference; D014162:Transfection
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000903:Antibiotics, Antineoplastic; D001381:Azepines; D015704:CD4 Antigens; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D011758:Pyrroles; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C097660:debromohymenialdisine; D004317:Doxorubicin; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; C505407:CASP3 protein, human; D053143:Caspase 2; D053148:Caspase 3; D020169:Caspases