High fructose drives the serine synthesis pathway in acute myeloid leukemic cells Journal Article
| Authors: | Jeong, S.; Savino, A. M.; Chirayil, R.; Barin, E.; Cheng, Y.; Park, S. M.; Schurer, A.; Mullarky, E.; Cantley, L. C.; Kharas, M. G.; Keshari, K. R. |
| Article Title: | High fructose drives the serine synthesis pathway in acute myeloid leukemic cells |
| 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. © 2020 Elsevier Inc. Excessive fructose intake has been implicated in cancer progression, and Jeong et al. show an unexpected metabolism of fructose in cancer cells. Acute myeloid leukemic cells upregulate the serine synthesis pathway to metabolize fructose-derived carbons, and targeting PHGDH, a rate-limiting enzyme in the serine synthesis pathway, significantly reduces the tumor burden in the presence of high fructose. © 2020 Elsevier Inc. |
| Keywords: | controlled study; human cell; nonhuman; comparative study; cell proliferation; animal cell; mouse; animal tissue; gene targeting; tumor volume; serine; animal experiment; animal model; leukemogenesis; glucose; oxidative stress; cell metabolism; reduced nicotinamide adenine dinucleotide; glutamine; glycine; carbon nuclear magnetic resonance; lactic acid; tumor microenvironment; 2 oxoglutaric acid; amino acid synthesis; acute myeloid leukemia; cell plasticity; nucleotide metabolism; cancer prognosis; 6 phosphofructokinase; redox; fructose; human; female; priority journal; article; lactate dehydrogenase a; genetic background; metabolic flux; oxygen consumption rate; acute myeloid leukemia cell line; fructose metabolism; thp-1 cell line; molm-13 cell line; k-562 cell line; in vivo isotope tracing; serine synthesis pathway; glucose transporter 5; fructose intake; high-fructose diet; kasumi-1 cell line; oci-aml-3 cell line |
| Journal Title: | Cell Metabolism |
| Volume: | 33 |
| Issue: | 1 |
| ISSN: | 1550-4131 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2021-01-05 |
| Start Page: | 145 |
| End Page: | 159.e6 |
| Language: | English |
| DOI: | 10.1016/j.cmet.2020.12.005 |
| PUBMED: | 33357456 |
| PROVIDER: | scopus |
| PMCID: | PMC8168776 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 February 2021 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work