A mitotic NADPH upsurge promotes chromosome segregation and tumour progression in aneuploid cancer cells
Menée à l'aide de lignées cellulaires, de modèles murins et d'échantillons tumoraux ainsi que d'échantillons tissulaires adjacents fixés au formaldéhyde et inclus en paraffine après prélèvement sur des patients atteints d'un cancer colorectal, cette étude met en évidence un mécanisme par lequel, dans les cellules cancéreuses aneuploïdes, l'augmentation de NADPH, induite par la glucose 6-phosphate déshydrogénase à l'entrée de la mitose, favorise la ségrégation chromosomique et la progression tumorale
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.
Nature Metabolism 2023