Uncovering metabolic reservoir cycles in MYC-transformed lymphoma B cells using stable isotope resolved metabolomics

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 glutaminelactate-glucose cycle was unforeseen. And third, we discovered that glutamine carbon is incorporated into gamma-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 MYCtransformed 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.

Automated summary

Recent metabolomic studies have revealed the existence of metabolic cycles involving glucose-NAAG-glutamate, glutamine-lactate-glucose, and glutamate-GABA-succinate in cancer cells. These cycles play crucial roles in storing carbon sources within oncogenic cells, impacting cell metabolism and potential therapeutic targets.