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

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

doi:10.1016/j.ccell.2016.09.006

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

Cancer Cell. 2016 Nov 14;30(5):779-791. doi: 10.1016/j.ccell.2016.09.006. Epub 2016 Oct 13.

Authors

Wen-Lian Chen¹, Yue-Ying Wang², Aihua Zhao³, Li Xia², Guoxiang Xie⁴, Mingming Su⁴, Linjing Zhao⁵, Jiajian Liu³, Chun Qu³, Runmin Wei⁵, Cynthia Rajani⁵, Yan Ni⁴, Zhen Cheng⁶, Zhu Chen², Sai-Juan Chen⁷, Wei Jia⁸

Affiliations

¹ State Key Laboratory of Medical Genomics, Department of Hematology, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China; University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
² State Key Laboratory of Medical Genomics, Department of Hematology, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
³ Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
⁴ Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China; University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
⁵ University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
⁶ Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Canary Center at Stanford for Cancer Early Detection, School of Medicine, Stanford University, Stanford, CA 94305, USA.
⁷ State Key Laboratory of Medical Genomics, Department of Hematology, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: sjchen@stn.sh.cn.
⁸ Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China; University of Hawaii Cancer Center, Honolulu, HI 96813, USA. Electronic address: wjia@cc.hawaii.edu.

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.

Keywords: GLUT5; SLC2A5; acute myeloid leukemia; fructose utilization.

Publication types

Comment

MeSH terms

Animals
Cell Line, Tumor
Cytarabine / administration & dosage*
Cytarabine / pharmacology
Drug Synergism
Fructose / metabolism*
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques / methods
Glucose Transporter Type 5 / genetics*
Glucose Transporter Type 5 / metabolism
Humans
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / genetics
Leukemia, Myeloid, Acute / metabolism
Mannitol / administration & dosage
Mannitol / analogs & derivatives*
Mannitol / pharmacology
Mice
Prognosis
Treatment Outcome
Up-Regulation

Substances

Glucose Transporter Type 5
SLC2A5 protein, human
Cytarabine
Fructose
Mannitol
2,5-anhydromannitol

Grants and funding

P30 CA071789/CA/NCI NIH HHS/United States