Identification of decatenation G2 checkpoint impairment independently of DNA damage G2 checkpoint in human lung cancer cell lines.
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.
Nakagawa
Taku
T
Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chukusa-ku, Nagoya 464-8681, Japan.
Hayashita
Yoji
Y
Maeno
Ken
K
Masuda
Akira
A
Sugito
Nobuyoshi
N
Osada
Hirotaka
H
Yanagisawa
Kiyoshi
K
Ebi
Hiromichi
H
Shimokata
Kaoru
K
Takahashi
Takashi
T
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
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