Enhanced Fructose Utilization Mediated by SLC2A5 Is a Unique Metabolic Feature of Acute Myeloid Leukemia with Therapeutic Potential

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2016 Oct 18

PMID 27746145

Citations 111

Authors

Wen-Lian Chen

Yue-Ying Wang

Aihua Zhao

Li Xia

Guoxiang Xie

Mingming Su

Linjing Zhao

Jiajian Liu

Chun Qu

Runmin Wei

Cynthia Rajani

Yan Ni

Zhen Cheng

Zhu Chen

Sai-Juan Chen

Wei Jia

Affiliations

Soon will be listed here.

Abstract

Rapidly proliferating leukemic progenitor cells consume substantial glucose, which may lead to glucose insufficiency in bone marrow. We show that acute myeloid leukemia (AML) cells are prone to fructose utilization with an upregulated fructose transporter GLUT5, which compensates for glucose deficiency. Notably, AML patients with upregulated transcription of the GLUT5-encoding gene SLC2A5 or increased fructose utilization have poor outcomes. Pharmacological blockage of fructose uptake ameliorates leukemic phenotypes and potentiates the cytotoxicity of the antileukemic agent, Ara-C. In conclusion, this study highlights enhanced fructose utilization as a metabolic feature of AML and a potential therapeutic target.

Citing Articles

New hope for the world cancer day.

Melino G, Bischof J, Chen W, Jia W, Juhl H, Kopeina G Biol Direct. 2025; 20(1):14.

PMID: 39901154 PMC: 11792201. DOI: 10.1186/s13062-025-00608-z.

AMPK-regulated glycerol excretion maintains metabolic crosstalk between reductive and energetic stress.

Zhai X, Yang R, Chu Q, Guo Z, Hou P, Li X Nat Cell Biol. 2025; 27(1):141-153.

PMID: 39747579 DOI: 10.1038/s41556-024-01549-x.

Immunosuppressive microenvironment in acute myeloid leukemia: overview, therapeutic targets and corresponding strategies.

Zha C, Yang X, Yang J, Zhang Y, Huang R Ann Hematol. 2024; 103(12):4883-4899.

PMID: 39607487 DOI: 10.1007/s00277-024-06117-9.

Mapping Natural Sugars Metabolism in Acute Myeloid Leukaemia Using 2D Nuclear Magnetic Resonance Spectroscopy.

Muhs C, Alshamleh I, Richter C, Serve H, Schwalbe H Cancers (Basel). 2024; 16(21).

PMID: 39518017 PMC: 11545164. DOI: 10.3390/cancers16213576.

Exploring fructose metabolism as a potential therapeutic approach for pancreatic cancer.

Wang C, Wang L, Zhao Q, Ma J, Li Y, Kuang J Cell Death Differ. 2024; 31(12):1625-1635.

PMID: 39406919 PMC: 11618635. DOI: 10.1038/s41418-024-01394-3.

References

Matsubara S, Ding Q, Miyazaki Y, Kuwahata T, Tsukasa K, Takao S . mTOR plays critical roles in pancreatic cancer stem cells through specific and stemness-related functions. Sci Rep. 2013; 3:3230. PMC: 3828572. DOI: 10.1038/srep03230. View

Wang Y, Zhao L, Wu C, Liu P, Shi L, Liang Y . C-KIT mutation cooperates with full-length AML1-ETO to induce acute myeloid leukemia in mice. Proc Natl Acad Sci U S A. 2011; 108(6):2450-5. PMC: 3038718. DOI: 10.1073/pnas.1019625108. View

Cairns R, Harris I, Mak T . Regulation of cancer cell metabolism. Nat Rev Cancer. 2011; 11(2):85-95. DOI: 10.1038/nrc2981. View

Wang J, Chen W, Li J, Wu S, Chen T, Zhu Y . Prognostic significance of 2-hydroxyglutarate levels in acute myeloid leukemia in China. Proc Natl Acad Sci U S A. 2013; 110(42):17017-22. PMC: 3801077. DOI: 10.1073/pnas.1315558110. View

Diers A, Broniowska K, Chang C, Hogg N . Pyruvate fuels mitochondrial respiration and proliferation of breast cancer cells: effect of monocarboxylate transporter inhibition. Biochem J. 2012; 444(3):561-71. PMC: 4898201. DOI: 10.1042/BJ20120294. View

Yang J, Dowden J, Tatibouet A, Hatanaka Y, Holman G . Development of high-affinity ligands and photoaffinity labels for the D-fructose transporter GLUT5. Biochem J. 2002; 367(Pt 2):533-9. PMC: 1222899. DOI: 10.1042/BJ20020843. View

Vijayaraghavan R, Kumar D, Dube S, Singh R, Pandey K, Bag B . Acute toxicity and cardio-respiratory effects of 2-deoxy-D-glucose: a promising radio sensitiser. Biomed Environ Sci. 2006; 19(2):96-103. View

Losman J, Looper R, Koivunen P, Lee S, Schneider R, McMahon C . (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science. 2013; 339(6127):1621-5. PMC: 3836459. DOI: 10.1126/science.1231677. View

Jang M, Kim S, Lee J . Cancer cell metabolism: implications for therapeutic targets. Exp Mol Med. 2013; 45:e45. PMC: 3809361. DOI: 10.1038/emm.2013.85. View

10.

Raez L, Papadopoulos K, Ricart A, Chiorean E, DiPaola R, Stein M . A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2012; 71(2):523-30. DOI: 10.1007/s00280-012-2045-1. View

11.

Lum J, Bui T, Gruber M, Gordan J, DeBerardinis R, Covello K . The transcription factor HIF-1alpha plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis. Genes Dev. 2007; 21(9):1037-49. PMC: 1855230. DOI: 10.1101/gad.1529107. View

12.

Liu H, Huang D, McArthur D, Boros L, Nissen N, Heaney A . Fructose induces transketolase flux to promote pancreatic cancer growth. Cancer Res. 2010; 70(15):6368-76. DOI: 10.1158/0008-5472.CAN-09-4615. View

13.

Jain M, Nilsson R, Sharma S, Madhusudhan N, Kitami T, Souza A . Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science. 2012; 336(6084):1040-4. PMC: 3526189. DOI: 10.1126/science.1218595. View

14.

Tabe Y, Konopleva M . Advances in understanding the leukaemia microenvironment. Br J Haematol. 2014; 164(6):767-78. PMC: 4381431. DOI: 10.1111/bjh.12725. View

15.

Doherty J, Cleveland J . Targeting lactate metabolism for cancer therapeutics. J Clin Invest. 2013; 123(9):3685-92. PMC: 3754272. DOI: 10.1172/JCI69741. View

16.

Pear W, Miller J, Xu L, Pui J, Soffer B, Quackenbush R . Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr/abl-transduced bone marrow. Blood. 1998; 92(10):3780-92. View

17.

Herst P, Howman R, Neeson P, Berridge M, Ritchie D . The level of glycolytic metabolism in acute myeloid leukemia blasts at diagnosis is prognostic for clinical outcome. J Leukoc Biol. 2010; 89(1):51-5. DOI: 10.1189/jlb.0710417. View

18.

Hulleman E, Kazemier K, Holleman A, VanderWeele D, Rudin C, Broekhuis M . Inhibition of glycolysis modulates prednisolone resistance in acute lymphoblastic leukemia cells. Blood. 2008; 113(9):2014-21. PMC: 4081395. DOI: 10.1182/blood-2008-05-157842. View

19.

Zhao Y, Butler E, Tan M . Targeting cellular metabolism to improve cancer therapeutics. Cell Death Dis. 2013; 4:e532. PMC: 3613838. DOI: 10.1038/cddis.2013.60. View

20.

Metzeler K, Hummel M, Bloomfield C, Spiekermann K, Braess J, Sauerland M . An 86-probe-set gene-expression signature predicts survival in cytogenetically normal acute myeloid leukemia. Blood. 2008; 112(10):4193-201. PMC: 2954679. DOI: 10.1182/blood-2008-02-134411. View