Energy restriction causes metaphase delay and chromosome mis-segregation in cancer cells
Energy restriction causes metaphase delay and chromosome mis-segregation in cancer cells
复制标题
能量限制导致癌细胞中期延迟和染色体错误分离
DOI：
10.1080/15384101.2021.1930679
复制
发表时间：
2021-05
期刊：
影响因子：
4.3
通讯作者：
Guo Jing
中科院分区：
文献类型：
--
作者：
Cheng Aoxing;Jiang Ya;Wang Ting;Yu Fazhi;Ishrat Iqra;Zhang Dongming;Ji Xiaoyang;Chen Minhua;Xiao Weihua;Li Qing;Zhang Kaiguang;Niu Gang;Shi Jue;Pan Yueyin;Yang Zhenye;Guo Jing
有丝分裂期间的ATP代谢需要与许多需要能量的活动相协调，特别是在癌细胞中，其代谢途径被重新编程以在营养缺乏的环境中维持快速增殖。尽管靶向能量代谢途径的策略在临床前癌症模型中显示出治疗效果，但正常细胞和癌细胞如何对能量短缺做出差异性反应尚不清楚。在这项研究中，使用延时显微镜，我们发现癌细胞在减少ATP（即能量）供应时以剂量依赖性方式显示独特的有丝分裂表型。当ATP浓度的减少是中等的，在有丝分裂中的染色体运动几乎没有受到影响，而中期-后期的过渡显着延长，由于姐妹动粒之间的张力降低，这延迟了满意的纺锤体组装检查点。ATP浓度的进一步降低导致着丝粒处的Aurora-B水平降低，从而导致中期延迟后染色体错误分离增加。与癌细胞相反，非转化细胞中的ATP限制诱导细胞周期停滞在间期，而不是导致有丝分裂缺陷。此外，对癌症患者数据库的数据挖掘显示，能量产生的特征与可能由有丝分裂缺陷引起的染色体不稳定性之间存在相关性。总之，这些结果表明，能量限制诱导正常细胞和癌细胞中的差异反应，仅在癌细胞中观察到染色体错误分离。这表明靶向能量代谢是一种潜在的癌症选择性治疗策略。
ABSTRACT ATP metabolism during mitosis needs to be coordinated with numerous energy-demanding activities, especially in cancer cells whose metabolic pathways are reprogramed to sustain rapid proliferation in a nutrient-deficient environment. Although strategies targeting the energy metabolic pathways have shown therapeutic efficacy in preclinical cancer models, how normal cells and cancer cells differentially respond to energy shortage is unclear. In this study, using time-lapse microscopy, we found that cancer cells displayed unique mitotic phenotypes in a dose-dependent manner upon decreasing ATP (i.e. energy) supply. When reduction in ATP concentration was moderate, chromosome movements in mitosis were barely affected, while the metaphase–anaphase transition was significantly prolonged due to reduced tension between the sister-kinetochores, which delayed the satisfaction of the spindle assembly checkpoint. Further reduction in ATP concentration led to a decreased level of Aurora-B at the centromere, resulting in increased chromosome mis-segregation after metaphase delay. In contrast to cancer cells, ATP restriction in non-transformed cells induced cell cycle arrest in interphase, rather than causing mitotic defects. In addition, data mining of cancer patient database showed a correlation between signatures of energy production and chromosomal instability possibly resulted from mitotic defects. Together, these results reveal that energy restriction induces differential responses in normal and cancer cells, with chromosome mis-segregation only observed in cancer cells. This points to targeting energy metabolism as a potentially cancer-selective therapeutic strategy.
登录
查看更多内容
影响因子：
29
作者：
Zhao Y;Jin J;Hu Q;Zhou HM;Yi J;Yu Z;Xu L;Wang X;Yang Y;Loscalzo J
通讯作者：
Loscalzo J
影响因子：
29
作者：
Pavlova NN;Thompson CB
通讯作者：
Thompson CB
影响因子：
3
作者：
Swerdlow, Russell H.;Lezi, E.;Aires, Daniel;Lu, Jianghua
通讯作者：
Lu, Jianghua
影响因子：
11.8
作者：
Wang, Zhaoqing;Fan, Ming;Candas, Demet;Zhang, Tie-Qiao;Qin, Lili;Eldridge, Angela;Wachsmann-Hogiu, Sebastian;Ahmed, Kazi M.;Chromy, Brett A.;Nantajit, Danupon;Duru, Nadire;He, Fuchu;Chen, Min;Finkel, Toren;Weinstein, Lee S.;Li, Jian Jian
通讯作者：
Li, Jian Jian
低剂量索拉非尼作为线粒体解偶联剂并改善非酒精性脂肪性肝炎
影响因子：
29
作者：
Jian, Chongshu;Fu, Jiajun;Cheng, Xu;Shen, Li-Jun;Ji, Yan-Xiao;Wang, Xiaoming;Pan, Shan;Tian, Han;Tian, Song;Liao, Rufang;Song, Kehan;Wang, Hai-Ping;Zhang, Xin;Wang, Yibin;Huang, Zan;She, Zhi-Gang;Zhang, Xiao-Jing;Zhu, Lihua;Li, Hongliang
通讯作者：
Li, Hongliang