1-C Metabolism-Serine, Glycine, Folates-In Acute Myeloid Leukemia

Overview

Journal Pharmaceuticals (Basel)

Publisher MDPI

Specialty Chemistry

Date 2021 Mar 3

PMID 33652666

Citations 8

Authors

Kanwal Mahmood

Ashkan Emadi

Affiliations

Soon will be listed here.

Abstract

Metabolic reprogramming contributes to tumor development and introduces metabolic liabilities that can be exploited to treat cancer. Studies in hematological malignancies have shown alterations in fatty acid, folate, and amino acid metabolism pathways in cancer cells. One-carbon (1-C) metabolism is essential for numerous cancer cell functions, including protein and nucleic acid synthesis and maintaining cellular redox balance, and inhibition of the 1-C pathway has yielded several highly active drugs, such as methotrexate and 5-FU. Glutamine depletion has also emerged as a therapeutic approach for cancers that have demonstrated dependence on glutamine for survival. Recent studies have shown that in response to glutamine deprivation leukemia cells upregulate key enzymes in the serine biosynthesis pathway, suggesting that serine upregulation may be a targetable compensatory mechanism. These new findings may provide opportunities for novel cancer treatments.

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References

Emadi A, Kapadia B, Bollino D, Bhandary B, Baer M, Niyongere S . Venetoclax and pegcrisantaspase for complex karyotype acute myeloid leukemia. Leukemia. 2020; 35(7):1907-1924. PMC: 10976320. DOI: 10.1038/s41375-020-01080-6. View

Jacque N, Ronchetti A, Larrue C, Meunier G, Birsen R, Willems L . Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition. Blood. 2015; 126(11):1346-56. PMC: 4608389. DOI: 10.1182/blood-2015-01-621870. View

Ducker G, Ghergurovich J, Mainolfi N, Suri V, Jeong S, Li S . Human SHMT inhibitors reveal defective glycine import as a targetable metabolic vulnerability of diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A. 2017; 114(43):11404-11409. PMC: 5664509. DOI: 10.1073/pnas.1706617114. View

Wang C, Wan X, Yu T, Huang Z, Shen C, Qi Q . Acetylation Stabilizes Phosphoglycerate Dehydrogenase by Disrupting the Interaction of E3 Ligase RNF5 to Promote Breast Tumorigenesis. Cell Rep. 2020; 32(6):108021. DOI: 10.1016/j.celrep.2020.108021. View

Yang M, Vousden K . Serine and one-carbon metabolism in cancer. Nat Rev Cancer. 2016; 16(10):650-62. DOI: 10.1038/nrc.2016.81. View

Barve A, Vega A, Shah P, Ghare S, Casson L, Wunderlich M . Perturbation of Methionine/S-adenosylmethionine Metabolism as a Novel Vulnerability in MLL Rearranged Leukemia. Cells. 2019; 8(11). PMC: 6912509. DOI: 10.3390/cells8111322. View

Ueland P, Hustad S, Schneede J, Refsum H, Vollset S . Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci. 2001; 22(4):195-201. DOI: 10.1016/s0165-6147(00)01675-8. View

Ducker G, Rabinowitz J . One-Carbon Metabolism in Health and Disease. Cell Metab. 2016; 25(1):27-42. PMC: 5353360. DOI: 10.1016/j.cmet.2016.08.009. View

Napoli M, Flores E . Another case for diet restriction: TAp73-expressing medulloblastomas are stunted by glutamine withdrawal. Genes Dev. 2017; 31(17):1715-1716. PMC: 5666670. DOI: 10.1101/gad.306837.117. View

10.

Gregory M, Nemkov T, Park H, Zaberezhnyy V, Gehrke S, Adane B . Targeting Glutamine Metabolism and Redox State for Leukemia Therapy. Clin Cancer Res. 2019; 25(13):4079-4090. PMC: 6642698. DOI: 10.1158/1078-0432.CCR-18-3223. View

11.

Maddocks O, Berkers C, Mason S, Zheng L, Blyth K, Gottlieb E . Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature. 2012; 493(7433):542-6. PMC: 6485472. DOI: 10.1038/nature11743. View

12.

de Jonge R, Hooijberg J, van Zelst B, Jansen G, Jansen G, van Zantwijk C . Effect of polymorphisms in folate-related genes on in vitro methotrexate sensitivity in pediatric acute lymphoblastic leukemia. Blood. 2005; 106(2):717-20. DOI: 10.1182/blood-2004-12-4941. View

13.

Gross M, Demo S, Dennison J, Chen L, Chernov-Rogan T, Goyal B . Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther. 2014; 13(4):890-901. DOI: 10.1158/1535-7163.MCT-13-0870. View

14.

Willems L, Jacque N, Jacquel A, Neveux N, Trovati Maciel T, Lambert M . Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia. Blood. 2013; 122(20):3521-32. PMC: 3829119. DOI: 10.1182/blood-2013-03-493163. View

15.

Adjei A . Pharmacology and mechanism of action of pemetrexed. Clin Lung Cancer. 2004; 5 Suppl 2:S51-5. DOI: 10.3816/clc.2004.s.003. View

16.

Lucena-Araujo A, Panepucci R, dos Santos G, Jacomo R, Santana-Lemos B, Lima A . The expression of DeltaNTP73, TATP73 and TP53 genes in acute myeloid leukaemia is associated with recurrent cytogenetic abnormalities and in vitro susceptibility to cytarabine cytotoxicity. Br J Haematol. 2008; 142(1):74-8. DOI: 10.1111/j.1365-2141.2008.07160.x. View

17.

van Geldermalsen M, Wang Q, Nagarajah R, Marshall A, Thoeng A, Gao D . ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer. Oncogene. 2015; 35(24):3201-8. PMC: 4914826. DOI: 10.1038/onc.2015.381. View

18.

Lucena-Araujo A, Kim H, Thome C, Jacomo R, Melo R, Bittencourt R . High ΔNp73/TAp73 ratio is associated with poor prognosis in acute promyelocytic leukemia. Blood. 2015; 126(20):2302-6. PMC: 4760128. DOI: 10.1182/blood-2015-01-623330. View

19.

Reid M, Allen A, Liu S, Liberti M, Liu P, Liu X . Serine synthesis through PHGDH coordinates nucleotide levels by maintaining central carbon metabolism. Nat Commun. 2018; 9(1):5442. PMC: 6303315. DOI: 10.1038/s41467-018-07868-6. View

20.

Nilsson R, Jain M, Madhusudhan N, Gustafsson Sheppard N, Strittmatter L, Kampf C . Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer. Nat Commun. 2014; 5:3128. PMC: 4106362. DOI: 10.1038/ncomms4128. View