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

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(T285) 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(T285) 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. In aneuploid cancer cells with high ROS levels, a mitotic NADPH upsurge is required for error-free mitosis and tumour progression and therefore constitutes a cell cycle-dependent metabolic vulnerability.

Automated summary

Research has found that redox metabolites in cancer cells fluctuate during the cell cycle, but the functional impacts of these metabolic oscillations are still unknown. A mitosis-specific upsurge of nicotinamide adenine dinucleotide phosphate (NADPH) has been discovered, which is essential for tumor progression. This upsurge is produced by glucose 6-phosphate dehydrogenase (G6PD) upon mitotic entry and neutralizes elevated reactive oxygen species (ROS), preventing ROS-induced inactivation of mitotic kinases and chromosome missegregation. The study reveals that aneuploid cancer cells with high ROS levels depend on a G6PD-mediated NADPH upsurge during mitosis to protect against ROS-induced chromosome missegregation, making this upsurge a cell cycle-dependent metabolic vulnerability.