title: Identification of decatenation G2 checkpoint impairment independently of DNA damage G2 checkpoint in human lung cancer cell lines.
abstract: It has been suggested that attenuation of the decatenation G(2) checkpoint function, which ensures sufficient chromatid decatenation by topoisomerase II before entering into mitosis, may contribute to the acquisition of genetic instability in cancer cells. To date, however, very little information is available on this type of checkpoint defect in human cancers. In this study, we report for the first time that a proportion of human lung cancer cell lines did not properly arrest before entering mitosis in the presence of a catalytic, circular cramp-forming topoisomerase II inhibitor ICRF-193, whereas the decatenation G(2) checkpoint impairment was present independently of the impaired DNA damage G(2) checkpoint. In addition, the presence of decatenation G(2) checkpoint dysfunction was found to be associated with diminished activation of ataxia-telangiectasia mutated in response to ICRF-193, suggesting the potential involvement of an upstream pathway sensing incompletely catenated chromatids. Interestingly, hypersensitivity to ICRF-193 was observed in cell lines with decatenation G(2) checkpoint impairment and negligible activation of ataxia-telangiectasia mutated. These findings suggest the possible involvement of decatenation G(2) checkpoint impairment in the development of human lung cancers, as well as the potential clinical implication of selective killing of lung cancer cells with such defects by this type of topoisomerase II inhibitor.
authors.affiliation: Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chukusa-ku, Nagoya 464-8681, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Yoji
authors.initials: Y
authors.lastname: Hayashita
authors.forename: Ken
authors.initials: K
authors.lastname: Maeno
authors.forename: Akira
authors.initials: A
authors.lastname: Masuda
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Sugito
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Osada
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yanagisawa
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ebi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Shimokata
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004249:DNA Damage; D004265:DNA Helicases / Q000235:genetics; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D054659:Diketopiperazines; D005090:Exodeoxyribonucleases; D016195:G2 Phase / Q000187:drug effects / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology; D053484:RecQ Helicases; D059005:Topoisomerase II Inhibitors; D000071657:Werner Syndrome Helicase
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D054659:Diketopiperazines; D010879:Piperazines; D059005:Topoisomerase II Inhibitors; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione; D005090:Exodeoxyribonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; D004250:DNA Topoisomerases, Type II