Glucose transporter 1-mediated glucose uptake is limiting for B-cell acute
lymphoblastic leukemia anabolic metabolism and resistance to apoptosis.
Authors Liu T, Kishton RJ, Macintyre AN, Gerriets VA, Xiang H, Liu X, Abel ED, Rizzieri
D, Locasale JW, Rathmell JC
Submitted By Submitted Externally on 3/4/2015
Status Published
Journal Cell death & disease
Year 2014
Date Published
Volume : Pages 5 : e1470
PubMed Reference 25321477
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.

Investigators with authorship
E. Dale AbelUniversity of Iowa