title: Glucose transporter 1-mediated glucose uptake is limiting for B-cell acute lymphoblastic leukemia anabolic metabolism and resistance to apoptosis.
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.
authors.affiliation: 1] Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA [2] Department of Immunology, Duke Cancer Institute and Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA.
authors.forename: T
authors.initials: T
authors.lastname: Liu
authors.affiliation: 1] Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA [2] Department of Immunology, Duke Cancer Institute and Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Kishton
authors.affiliation: 1] Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA [2] Department of Immunology, Duke Cancer Institute and Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA.
authors.forename: A N
authors.initials: AN
authors.lastname: Macintyre
authors.affiliation: 1] Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA [2] Department of Immunology, Duke Cancer Institute and Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA.
authors.forename: V A
authors.initials: VA
authors.lastname: Gerriets
authors.affiliation: 1] Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA [2] Department of Immunology, Duke Cancer Institute and Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA.
authors.forename: H
authors.initials: H
authors.lastname: Xiang
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14850, USA.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: E D
authors.initials: ED
authors.lastname: Abel
authors.affiliation: Division of Cell Therapy, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: D
authors.initials: D
authors.lastname: Rizzieri
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14850, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Locasale
authors.affiliation: 1] Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA [2] Department of Immunology, Duke Cancer Institute and Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Rathmell
mesh_terms: D000332:Aerobiosis / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology; D018450:Disease Progression; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D058990:Molecular Targeted Therapy; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D051272:Glucose Transporter Type 1; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C495677:SLC2A1 protein, human; D003847:Deoxyglucose; D005947:Glucose