한빛사논문
Sangmoo Jeong1,2,6, Angela Maria Savino2,3,6, Rachel Chirayil1,2, Ersilia Barin2,3, Yuanming Cheng2,3, Sun-Mi Park2,3, Alexandra Schurer2,3, Edouard Mullarky4,5, Lewis C. Cantley4,5, Michael G. Kharas2,3,*, Kayvan R. Keshari1,2,7,*
1Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
2Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
3Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
4Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA
5Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
6These authors contributed equally
7Lead Contact
*Corresponding author
Abstract
A significant increase in dietary fructose consumption has been implicated as a potential driver of cancer. Metabolic adaptation of cancer cells to utilize fructose confers advantages for their malignant growth, but compelling therapeutic targets have not been identified. Here, we show that fructose metabolism of leukemic cells can be inhibited by targeting the de novo serine synthesis pathway (SSP). Leukemic cells, unlike their normal counterparts, become significantly dependent on the SSP in fructose-rich conditions as compared to glucose-rich conditions. This metabolic program is mediated by the ratio of redox cofactors, NAD+/NADH, and the increased SSP flux is beneficial for generating alpha-ketoglutarate from glutamine, which allows leukemic cells to proliferate even in the absence of glucose. Inhibition of PHGDH, a rate-limiting enzyme in the SSP, dramatically reduces leukemia engraftment in mice in the presence of high fructose, confirming the essential role of the SSP in the metabolic plasticity of leukemic cells.
Keywords : metabolic flux, in vivo isotope tracing, redox, serine synthesis pathway
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