Nitta Masayuki, Kobayashi Osamu, Honda Shinobu, Hirota Toru, Kuninaka Shinji, Marumoto Tomotoshi, Ushio Yukitaka, Saya Hideyuki
Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, University of Kumamoto, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Oncogene. 2004 Aug 26;23(39):6548-58. doi: 10.1038/sj.onc.1207873.
Mitotic catastrophe is an important mechanism for the induction of cell death in cancer cells by antineoplastic agents that damage DNA. This process is facilitated by defects in the G1 and G2 checkpoints of the cell cycle that are apparent in most cancer cells and which allow the cells to enter mitosis with DNA damage. We have now characterized the dynamics of mitotic catastrophe induced by DNA-damaging agents in p53-deficient cancer cells. Cells that entered mitosis with DNA damage transiently arrested at metaphase for more than 10 h without segregation of chromosomes and subsequently died directly from metaphase. In those metaphase arrested precatastrophic cells, anaphase-promoting complex appeared to be inactivated and BubR1 was persistently localized at kinetochores, suggesting that spindle checkpoint is activated after the DNA damage. Furthermore, suppression of spindle checkpoint function by BubR1 or Mad2 RNA interference in the DNA damaged cells led to escape from catastrophic death and to subsequent abnormal mitosis. Dysfunction of the spindle checkpoint in p53-deficient cancer cells is thus likely a critical factor in resistance to DNA-damaging therapeutic agents.
有丝分裂灾难是抗肿瘤药物诱导癌细胞死亡的重要机制，这些药物会损伤DNA。这个过程由细胞周期G1和G2检查点的缺陷促成，这些缺陷在大多数癌细胞中很明显，使细胞能够带着DNA损伤进入有丝分裂。我们现在已经描述了p53缺陷癌细胞中DNA损伤剂诱导的有丝分裂灾难的动态过程。带着DNA损伤进入有丝分裂的细胞在中期短暂停滞超过10小时，染色体不分离，随后直接从中期死亡。在那些中期停滞的灾难前细胞中，后期促进复合物似乎失活，BubR1持续定位于动粒，这表明DNA损伤后纺锤体检查点被激活。此外，在DNA损伤细胞中通过BubR1或Mad2 RNA干扰抑制纺锤体检查点功能导致逃脱灾难性死亡并随后出现异常有丝分裂。因此，p53缺陷癌细胞中纺锤体检查点功能障碍可能是对DNA损伤治疗药物耐药的关键因素。
