MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Department of Digestive Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Nat Metab. 2023 Jul;5(7):1141-1158. doi: 10.1038/s42255-023-00832-9. Epub 2023 Jun 22.
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 BAG3 phosphorylation 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 BAG3 phosphorylation 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.
氧化还原代谢物在癌细胞的细胞周期中会发生波动，但这种代谢波动的功能影响尚不清楚。在这里，我们揭示了一种有丝分裂特异性的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）激增，它对肿瘤的进展是必不可少的。具体来说，NADPH 是由葡萄糖 6-磷酸脱氢酶（G6PD）在有丝分裂进入时产生的，它可以中和升高的活性氧（ROS），防止 ROS 介导的有丝分裂激酶失活和染色体错分。G6PD 的有丝分裂激活依赖于其共伴侣蛋白 BAG3 第 285 位苏氨酸的磷酸化，这导致抑制性 BAG3 的解离。阻止 BAG3 磷酸化会诱导肿瘤抑制。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。在一组微卫星稳定结直肠癌患者中，高 BAG3 磷酸化与预后较差相关。我们的研究表明，具有高水平 ROS 的非整倍体癌细胞依赖于 G6PD 介导的有丝分裂 NADPH 激增来保护它们免受 ROS 诱导的染色体错分。
