Journal article
DNA replication stress underpins the vulnerability to oxidative phosphorylation inhibition in colorectal cancer
XH Zhao, MM Han, QQ Yan, YM Yue, K Ye, YY Zhang, L Teng, L Xu, XJ Shi, T La, YC Feng, R Xu, VK Narayana, DP De Souza, LE Quek, J Holst, T Liu, MA Baker, RF Thorne, XD Zhang Show all
Cell Death and Disease | SPRINGERNATURE | Published : 2025
Open access
Abstract
Mitochondrial oxidative phosphorylation (OXPHOS) is a therapeutic vulnerability in glycolysis-deficient cancers. Here we show that inhibiting OXPHOS similarly suppresses the proliferation and tumorigenicity of glycolytically competent colorectal cancer (CRC) cells in vitro and in patient-derived CRC xenografts. While the increased glycolytic activity rapidly replenished the ATP pool, it did not restore the reduced production of aspartate upon OXPHOS inhibition. This shortage in aspartate, in turn, caused nucleotide deficiencies, leading to S phase cell cycle arrest, replication fork stalling, and enrichment of the p53 pathway, manifestations of replication stress. The addition of purine nucl..
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Awarded by Walter and Eliza Hall Institute of Medical Research
Funding Acknowledgements
The authors thank Professor Marco Herold (Walter and Eliza Hall Institute of Medical Research, Australia) for providing the FH1-tUTG plasmid. This work was supported by the National Health and Medical Research Council (XDZ, 2016686; LJ, 1177087), Australia; the Cancer Council NSW (XDZ, RG21-10), Australia; the National Natural Science Foundation of China (LJ, 82173138; TL, 82072790), China.