Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells.
Because MYC plays a causal role in many human cancers, including those with hypoxic and nutrient-poor tumor microenvironments, we have determined the metabolic responses of a MYC-inducible human Burkitt lymphoma model P493 cell line to aerobic and hypoxic conditions, and to glucose deprivation, using stable isotope-resolved metabolomics. Using [U-(13)C]-glucose as the tracer, both glucose consumption and lactate production were increased by MYC expression and hypoxia. Using [U-(13)C,(15)N]-glutamine as the tracer, glutamine import and metabolism through the TCA cycle persisted under hypoxia, and glutamine contributed significantly to citrate carbons. Under glucose deprivation, glutamine-derived fumarate, malate, and citrate were significantly increased. Their (13)C-labeling patterns demonstrate an alternative energy-generating glutaminolysis pathway involving a glucose-independent TCA cycle. The essential role of glutamine metabolism in cell survival and proliferation under hypoxia and glucose deficiency makes them susceptible to the glutaminase inhibitor BPTES and hence could be targeted for cancer therapy.
Division of Gastrointestinal and Liver Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. annele@jhmi.edu
Anne
A
Le
Andrew N
AN
Lane
Max
M
Hamaker
Sminu
S
Bose
Arvin
A
Gouw
Joseph
J
Barbi
Takashi
T
Tsukamoto
Camilio J
CJ
Rojas
Barbara S
BS
Slusher
Haixia
H
Zhang
Lisa J
LJ
Zimmerman
Daniel C
DC
Liebler
Robbert J C
RJ
Slebos
Pawel K
PK
Lorkiewicz
Richard M
RM
Higashi
Teresa W M
TW
Fan
Chi V
CV
Dang
D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D002247:Carbon Isotopes / Q000737:chemistry; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D019343:Citric Acid / Q000378:metabolism; D002952:Citric Acid Cycle / Q000502:physiology*; D005650:Fumarates / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005972:Glutaminase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D007553:Isotope Labeling; D008293:Malates / Q000378:metabolism; D010084:Oxidation-Reduction; D013440:Sulfides / Q000494:pharmacology; D013830:Thiadiazoles / Q000494:pharmacology
D002247:Carbon Isotopes; D005650:Fumarates; D008293:Malates; D013440:Sulfides; D013830:Thiadiazoles; C523193:bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide; D005973:Glutamine; D019343:Citric Acid; D005972:Glutaminase; D005947:Glucose