A mitotic NADPH upsurge promotes chromosome segregation and tumour progression in aneuploid cancer cells
A mitotic NADPH upsurge promotes chromosome segregation and tumour progression in aneuploid cancer cells
复制标题
DOI：
10.1038/s42255-023-00832-9
复制
发表时间：
2023-06
影响因子：
20.8
通讯作者：
Aoxing Cheng;Tianbing Xu;Weiyi You;Ting Wang;D. Zhang;Huimin Guo;Haiyan Zhang;Xin Pan
中科院分区：
文献类型：
--
作者：
Aoxing Cheng;Tianbing Xu;Weiyi You;Ting Wang;D. Zhang;Huimin Guo;Haiyan Zhang;Xin Pan
已经观察到氧化还原代谢物在癌细胞的细胞周期中波动，但这种代谢振荡的功能影响仍然未知。在这里，我们发现了一个有丝分裂特异性的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的激增，这是肿瘤进展所必需的。具体而言，NADPH由葡萄糖6-磷酸脱氢酶（G6 PD）在有丝分裂进入时产生，其中和升高的活性氧（ROS）并防止ROS介导的有丝分裂激酶失活和染色体错误分离。G6 PD的有丝分裂激活依赖于其共伴侣蛋白BAG 3在苏氨酸285处的磷酸化，这导致抑制性BAG 3的解离。阻断BAG 3 T285磷酸化诱导肿瘤抑制。在具有高水平ROS的非整倍体癌细胞中存在有丝分裂NADPH激增，而在近二倍体癌细胞中几乎观察不到。高BAG 3 T285磷酸化与微卫星稳定性结直肠癌患者队列预后不良相关我们的研究表明，具有高水平ROS的非整倍体癌细胞依赖于有丝分裂中G6 PD介导的NADPH激增，以保护它们免受ROS诱导的染色体错误分离。
Redox metabolites have been observed to fluctuate through the cell cycle in cancer cells, but the functional impacts of such metabolic oscillations remain unknown. Here, we uncover a mitosis-specific nicotinamide adenine dinucleotide phosphate (NADPH) upsurge that is essential for tumour progression. Specifically, NADPH is produced by glucose 6-phosphate dehydrogenase (G6PD) upon mitotic entry, which neutralizes elevated reactive oxygen species (ROS) and prevents ROS-mediated inactivation of mitotic kinases and chromosome missegregation. Mitotic activation of G6PD depends on the phosphorylation of its co-chaperone protein BAG3 at threonine 285, which results in dissociation of inhibitory BAG3. Blocking BAG3T285phosphorylation induces tumour suppression. A mitotic NADPH upsurge is present in aneuploid cancer cells with high levels of ROS, while nearly unobservable in near-diploid cancer cells. High BAG3T285phosphorylation is associated with worse prognosis in a cohort of patients with microsatellite-stable colorectal cancer. Our study reveals that aneuploid cancer cells with high levels of ROS depend on a G6PD-mediated NADPH upsurge in mitosis to protect them from ROS-induced chromosome missegregation.