High Fructose Drives the Serine Synthesis Pathway in Acute Myeloid Leukemic Cells

Sangmoo Jeong, Angela Maria Savino, Rachel Chirayil, Ersilia Barin, Yuanming Cheng, Sun Mi Park, Alexandra Schurer, Edouard Mullarky, Lewis C. Cantley, Michael G. Kharas*, Kayvan R. Keshari*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)145-159.e6
JournalCell Metabolism
Volume33
Issue number1
DOIs
StatePublished - 5 Jan 2021
Externally publishedYes

Keywords

  • in vivo isotope tracing
  • metabolic flux
  • redox
  • serine synthesis pathway

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