TY - JOUR
T1 - A mitotic NADPH upsurge promotes chromosome segregation and tumour progression in aneuploid cancer cells
AU - Cheng, Aoxing
AU - Xu, Tian
AU - You, Weiyi
AU - Wang, Ting
AU - Zhang, Dongming
AU - Guo, Huimin
AU - Zhang, Haiyan
AU - Pan, Xin
AU - Wang, Yucai
AU - Liu, Liu
AU - Zhang, Kaiguang
AU - Shi, Jue
AU - Yao, Xuebiao
AU - Guo, Jing
AU - Yang, Zhenye
N1 - We thank Y. Yang and Y. Zhao at the East China University of Science and Technology for providing the iNap1 sensor plasmids; and B. Li at Capital Medical University for providing materials and reagents. This work was supported by the National Key R&D Program of China (2022YFA1303100 to X.Y. and Z.Y.), the National Science Foundation of China (92057104 to Z.Y., 31970670 and 32170736 to J.G. and 32000528 to A.C.) and the Fundamental Research Funds for the Central Universities (WK2070000189 to A.C., YD9100002011 and YD9100002028 to Z.Y.). This work was also supported in part by the Open Project of the CAS Key Laboratory of Innate Immunity and Chronic Disease and Research Funds of the Center for Advanced Interdisciplinary Science and Biomedicine of IHM of the USTC (QYPY20220017 to Z.Y.), the ‘Laboratory for Synthetic Chemistry and Chemical Biology’ under the Health@InnoHK programme by the Innovation and Technology Commission of Hong Kong and the Hong Kong Research Grant Council (T12-710/16-R to J.S.). All correspondence and requests for materials should be addressed to Z.Y. ([email protected]).
Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2023/7
Y1 - 2023/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85162950869&partnerID=8YFLogxK
U2 - 10.1038/s42255-023-00832-9
DO - 10.1038/s42255-023-00832-9
M3 - Journal article
C2 - 37349486
AN - SCOPUS:85162950869
SN - 2522-5812
VL - 5
SP - 1141
EP - 1158
JO - Nature Metabolism
JF - Nature Metabolism
IS - 7
ER -
