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.
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.
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