Glucose transporter 1-mediated glucose uptake is limiting for B-cell acute lymphoblastic leukemia anabolic metabolism and resistance to apoptosis

T Liu; R J Kishton; A N Macintyre; V A Gerriets; H Xiang; X Liu; E D Abel; D Rizzieri; J W Locasale; J C Rathmell

doi:10.1038/cddis.2014.431

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Glucose transporter 1-mediated glucose uptake is limiting for B-cell acute lymphoblastic leukemia anabolic metabolism and resistance to apoptosis

Journal article

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Glucose transporter 1-mediated glucose uptake is limiting for B-cell acute lymphoblastic leukemia anabolic metabolism and resistance to apoptosis

T Liu, R J Kishton, A N Macintyre, V A Gerriets, H Xiang, X Liu, E D Abel, D Rizzieri, J W Locasale and J C Rathmell

Cell death & disease, Vol.5(10), pp.e1470-e1470

10/16/2014

DOI: 10.1038/cddis.2014.431

PMCID: PMC4237255

PMID: 25321477

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Abstract

The metabolic profiles of cancer cells have long been acknowledged to be altered and to provide new therapeutic opportunities. In particular, a wide range of both solid and liquid tumors use aerobic glycolysis to supply energy and support cell growth. This metabolic program leads to high rates of glucose consumption through glycolysis with secretion of lactate even in the presence of oxygen. Identifying the limiting events in aerobic glycolysis and the response of cancer cells to metabolic inhibition is now essential to exploit this potential metabolic dependency. Here, we examine the role of glucose uptake and the glucose transporter Glut1 in the metabolism and metabolic stress response of BCR-Abl+ B-cell acute lymphoblastic leukemia cells (B-ALL). B-ALL cells were highly glycolytic and primary human B-ALL samples were dependent on glycolysis. We show B-ALL cells express multiple glucose transporters and conditional genetic deletion of Glut1 led to a partial loss of glucose uptake. This reduced glucose transport capacity, however, was sufficient to metabolically reprogram B-ALL cells to decrease anabolic and increase catabolic flux. Cell proliferation decreased and a limited degree of apoptosis was also observed. Importantly, Glut1-deficient B-ALL cells failed to accumulate in vivo and leukemic progression was suppressed by Glut1 deletion. Similarly, pharmacologic inhibition of aerobic glycolysis with moderate doses of 2-deoxyglucose (2-DG) slowed B-ALL cell proliferation, but extensive apoptosis only occurred at high doses. Nevertheless, 2-DG induced the pro-apoptotic protein Bim and sensitized B-ALL cells to the tyrosine kinase inhibitor Dasatinib in vivo. Together, these data show that despite expression of multiple glucose transporters, B-ALL cells are reliant on Glut1 to maintain aerobic glycolysis and anabolic metabolism. Further, partial inhibition of glucose metabolism is sufficient to sensitize cancer cells to specifically targeted therapies, suggesting inhibition of aerobic glycolysis as a plausible adjuvant approach for B-ALL therapies.

Proto-Oncogene Proteins - metabolism

Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology

Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism

Apoptosis - drug effects

Humans

Glucose Transporter Type 1 - metabolism

Aerobiosis - drug effects

Molecular Targeted Therapy

Glycolysis - drug effects

Disease Progression

Apoptosis Regulatory Proteins - metabolism

Bcl-2-Like Protein 11

Deoxyglucose - pharmacology

Gene Deletion

Cell Line, Tumor

Glucose - metabolism

Cell Proliferation - drug effects

Membrane Proteins - metabolism

Metabolic Networks and Pathways - drug effects

Details

Title: Subtitle: Glucose transporter 1-mediated glucose uptake is limiting for B-cell acute lymphoblastic leukemia anabolic metabolism and resistance to apoptosis
Creators: T Liu - 1] Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA Department of Immunology, Duke Cancer Institute and Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA
R J Kishton - 1] Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA Department of Immunology, Duke Cancer Institute and Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA
A N Macintyre - 1] Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA Department of Immunology, Duke Cancer Institute and Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA
V A Gerriets - 1] Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA Department of Immunology, Duke Cancer Institute and Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA
H Xiang - 1] Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA Department of Immunology, Duke Cancer Institute and Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA
X Liu - Division of Nutritional Sciences, Cornell University, Ithaca, NY 14850, USA
E D Abel - Fraternal Order of Eagles Diabetes Research Center, Division of Endocrinology and Metabolism, Department of Medicine, Carver College of Medicine University of Iowa, Iowa City, IA 52242, USA
D Rizzieri - Division of Cell Therapy, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
J W Locasale - Division of Nutritional Sciences, Cornell University, Ithaca, NY 14850, USA
J C Rathmell - 1] Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA Department of Immunology, Duke Cancer Institute and Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA
Resource Type: Journal article
Publication Details: Cell death & disease, Vol.5(10), pp.e1470-e1470
DOI: 10.1038/cddis.2014.431
PMID: 25321477
PMCID: PMC4237255
NLM abbreviation: Cell Death Dis
ISSN: 2041-4889
eISSN: 2041-4889
Publisher: England
Grant note: R00 CA168997 / NCI NIH HHS P30 CA014236 / NCI NIH HHS U01HL087947 / NHLBI NIH HHS U01 HL087947 / NHLBI NIH HHS R01CA123350 / NCI NIH HHS F31 CA183529 / NCI NIH HHS F31CA183529 / NCI NIH HHS R01 CA123350 / NCI NIH HHS R03 AI106835 / NIAID NIH HHS R03AI106835 / NIAID NIH HHS
Language: English
Date published: 10/16/2014
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984025275802771

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