A mitotic NADPH upsurge promotes chromosome segregation and tumour progression in aneuploid cancer cells

Aoxing Cheng, Tian Xu, Weiyi You, Ting Wang, Dongming Zhang, Huimin Guo, Haiyan Zhang, Xin Pan, Yucai Wang, Liu Liu, Kaiguang Zhang, Jue Shi, Xuebiao Yao, Jing Guo*, Zhenye Yang*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

4 Citations (Scopus)

Abstract

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 BAG3T285 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 BAG3T285 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.

Original languageEnglish
Pages (from-to)1141-1158
Number of pages18
JournalNature Metabolism
Volume5
Issue number7
Early online date22 Jun 2023
DOIs
Publication statusPublished - Jul 2023

Scopus Subject Areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Physiology (medical)
  • Cell Biology

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