Identification of decatenation G2 checkpoint impairment independently of DNA damage G2 checkpoint in human lung cancer cell lines
Identification of decatenation G2 checkpoint impairment independently of DNA damage G2 checkpoint in human lung cancer cell lines
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DOI：
10.1158/0008-5472.can-04-0871
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发表时间：
2004-07-15
期刊：
影响因子：
11.2
通讯作者：
Takahashi, T
中科院分区：
文献类型：
--
作者：
Nakagawa, T;Hayashita, Y;Takahashi, T
有研究表明，去连环化G（2）检查点功能的减弱可能有助于癌细胞遗传不稳定性的获得，该功能确保了在进入有丝分裂之前通过拓扑异构酶11进行足够的染色单体去连环化。然而，迄今为止，关于人类癌症中这种类型的检查点缺陷的信息非常少。在这项研究中，我们首次报道了一部分人肺癌细胞系在催化性环状痉挛形成拓扑异构酶11抑制剂ICRF-193存在下，在进入有丝分裂前没有适当地停滞，而去连环化G（2）检查点损伤独立于受损的DNA损伤G（2）检查点。此外，发现去连环化G（2）检查点功能障碍的存在与ICRF-193引起的共济失调-毛细血管扩张突变的激活减弱有关，这表明上游途径可能参与了感应不完全连环染色单体的过程。有趣的是，在具有脱钙G（2）检查点损伤和可忽略的共济失调血管扩张突变激活的细胞系中观察到对ICRF-193的超敏反应。这些发现表明去连环化G（2）检查点损伤可能参与人类肺癌的发展，以及这种类型的拓扑异构酶11抑制剂选择性杀死具有此类缺陷的肺癌细胞的潜在临床意义。
It has been suggested that attenuation of the decatenation G(2) checkpoint function, which ensures sufficient chromatid decatenation by topoisomerase 11 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 11 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. Interest ingly, hypersensitivity to ICRF-193 was observed in cell lines with decalenation G(2) checkpoint impairment and negligible activation of ataxiatelangiectasia 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 11 inhibitor.