Melanoma cells crave glutamine since they can overuse this essential nutrient as an additional source of energy and carbon. These recent findings represent an additional support for a treatment strategy limiting glutamine supply to tumor cells through nutritional modification or inhibitors of the glutamine uptake process.
David Scott, who is the senior author of the study published in Oncotarget, stated in a press release: “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 cycle. 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 tricarboxylic acid cycle, also known by Krebs cycle, is a metabolic cycle in which cells generate ATP [high-energy molecule] to create energy, a process occurring within mitochondria. Cells use this fuel to carry their tasks and in healthy conditions glutamine is used to create cellular nitrogen supplies.
“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. 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,” said Boris Ratnikov, leading author of the paper.
Researchers managed to find the key enzymatic pathways that control the entry and exit of glutamine and its derivatives in and out of the Krebs cycle.
“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. 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,” concluded Dr. Scott.