TY - JOUR
T1 - Uncovering metabolic reservoir cycles in MYC-transformed lymphoma B cells using stable isotope resolved metabolomics
AU - Hoang, Giang
AU - Zhang, Cissy
AU - Attarwala, Nabeel
AU - Jung, Jin G.
AU - Cooper, Arthur J.L.
AU - Le, Anne
N1 - Publisher Copyright:
© 2021 The Authors
PY - 2021/11/1
Y1 - 2021/11/1
N2 - The use of metabolomic technologies and stable isotope labeling recently enabled us to discover an unexpected role of N-acetyl-aspartyl-glutamate (NAAG): NAAG is a glutamate reservoir for cancer cells. In the current study, we first found that glucose carbon contributes to the formation of NAAG and its precursors via glycolysis, demonstrating the existence of a glucose-NAAG-glutamate cycle in cancer cells. Second, we found that glucose carbon and, unexpectedly, glutamine carbon contribute to the formation of lactate via glutaminolysis. Importantly, lactate carbon can be incorporated into glucose via gluconeogenesis, demonstrating the existence of a glutamine-lactate-glucose cycle. While a glucose-lactate-glucose cycle was expected, the finding of a glutamine-lactate-glucose cycle was unforeseen. And third, we discovered that glutamine carbon is incorporated into γ-aminobutyric acid (GABA), revealing a glutamate-GABA-succinate cycle. Thus, NAAG, lactate, and GABA can play important roles as storage molecules for glutamate, glucose, and succinate carbon in oncogenic MYC-transformed P493 lymphoma B cells (MYC-ON cells) but not in non-oncogenic MYC-OFF cells. Altogether, examining the isotopic labeling patterns of metabolites derived from labeled 13C6-glucose or 13C515N2-glutamine helped reveal the presence of what we have named “metabolic reservoir cycles” in oncogenic cells.
AB - The use of metabolomic technologies and stable isotope labeling recently enabled us to discover an unexpected role of N-acetyl-aspartyl-glutamate (NAAG): NAAG is a glutamate reservoir for cancer cells. In the current study, we first found that glucose carbon contributes to the formation of NAAG and its precursors via glycolysis, demonstrating the existence of a glucose-NAAG-glutamate cycle in cancer cells. Second, we found that glucose carbon and, unexpectedly, glutamine carbon contribute to the formation of lactate via glutaminolysis. Importantly, lactate carbon can be incorporated into glucose via gluconeogenesis, demonstrating the existence of a glutamine-lactate-glucose cycle. While a glucose-lactate-glucose cycle was expected, the finding of a glutamine-lactate-glucose cycle was unforeseen. And third, we discovered that glutamine carbon is incorporated into γ-aminobutyric acid (GABA), revealing a glutamate-GABA-succinate cycle. Thus, NAAG, lactate, and GABA can play important roles as storage molecules for glutamate, glucose, and succinate carbon in oncogenic MYC-transformed P493 lymphoma B cells (MYC-ON cells) but not in non-oncogenic MYC-OFF cells. Altogether, examining the isotopic labeling patterns of metabolites derived from labeled 13C6-glucose or 13C515N2-glutamine helped reveal the presence of what we have named “metabolic reservoir cycles” in oncogenic cells.
KW - GABA
KW - Lactate
KW - Metabolic reservoir cycles
KW - NAAG
KW - Oncogenic cells
KW - Storage molecules
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U2 - 10.1016/j.ab.2021.114206
DO - 10.1016/j.ab.2021.114206
M3 - Article
C2 - 33894159
AN - SCOPUS:85115969994
SN - 0003-2697
VL - 632
JO - Analytical biochemistry
JF - Analytical biochemistry
M1 - 114206
ER -