“We have shown for the first time how glutamine is metabolized by melanoma cells and how their appetite for it is driven by the tricarboxylic acid (TCA) cycle,” said David Scott, Ph.D., staff scientist at Sanford-Burnham and senior author of the paper. “Their requirement for glutamine is in contrast to the nutritional requirements of normal melanocytes and is completely independent of the DNA mutations such as BRAF, NRAS, and p53 that transform healthy melanocytes to become tumorigenic.”
The TCA cycle, also known as the Krebs cycle, is a metabolic cycle that occurs in the mitochondria of cells to generate a pool of chemical energy in the form of ATP—the high-energy molecule that provides the fuel for cells to carry out their functions. Under normal healthy conditions, glutamine is primarily used to create a supply of nitrogen for cells.
“Our finding that the need for glutamine is unrelated to the various oncogenic mutations that drive melanoma means that a glutamine starvation approach may work broadly against many melanoma tumors,” said Boris Ratnikov, Ph.D., staff scientist at Sanford-Burnham and lead author of the paper. “Moreover, given that melanoma patients typically become resistant to therapy and/or they relapse, there is an urgent need for new treatment interventions for patients with this often deadly disease.”
Using a combination of melanoma cell lines and metabolomic technology, the researchers established the key enzymatic pathways that drive both the entry and exit of glutamine and glutamine derivatives in and out of the TCA cycle. They found that glutamine was required to maintain the TCA cycle as well as for asparagine synthesis. Asparagine is one of the most common amino acids and plays an important role in glycosylation—the process of adding sugar molecules to proteins for proper functioning.
“Melanoma’s addiction to glutamine is like an Achilles’ heel. It represents a vulnerability that we can target while sparing normal melanocytes that can survive without glutamine,” said Scott. “The amino acid starvation strategy is currently used successfully to treat certain types of leukemia, so the approach is not without precedent. Our next step is to further our understanding of inter and intracellular glutamine transport, the role of asparagine in the process, and to verify the glutamate requirement of melanoma in vivo.”
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Boris Ratnikov is a staff scientist in the lab of Jeffrey W. Smith, Ph.D., professor in the Cell Death and Survival Networks Program, and David Scott is a staff scientist in the lab of Andrei Osterman, Ph.D., in the Bioinformatics and Structural Biology Program at Sanford-Burnham.
Sanford-Burnham study participants included Boris Ratnikov, Pedro Aza-Blanc, Ze’ev Ronai, Jeffrey W. Smith, Andrei L. Osterman, and David A. Scott.
This study was funded by NIH grants CA-128814 and CA-182209.
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