Glutamate and asparagine cataplerosis underlie glutamine addiction in melanoma.
Glutamine dependence is a prominent feature of cancer metabolism, and here we show that melanoma cells, irrespective of their oncogenic background, depend on glutamine for growth. A quantitative audit of how carbon from glutamine is used showed that TCA-cycle-derived glutamate is, in most melanoma cells, the major glutamine-derived cataplerotic output and product of glutaminolysis. In the absence of glutamine, TCA cycle metabolites were liable to depletion through aminotransferase-mediated α-ketoglutarate-to-glutamate conversion and glutamate secretion. Aspartate was an essential cataplerotic output, as melanoma cells demonstrated a limited capacity to salvage external aspartate. Also, the absence of asparagine increased the glutamine requirement, pointing to vulnerability in the aspartate-asparagine biosynthetic pathway within melanoma metabolism. In contrast to melanoma cells, melanocytes could grow in the absence of glutamine. Melanocytes use more glutamine for protein synthesis rather than secreting it as glutamate and are less prone to loss of glutamate and TCA cycle metabolites when starved of glutamine.
Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
Boris
B
Ratnikov
Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
Pedro
P
Aza-Blanc
Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
Ze'ev A
ZA
Ronai
Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
Jeffrey W
JW
Smith
Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
Andrei L
AL
Osterman
Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
David A
DA
Scott
D001216:Asparagine / Q000378:metabolism*; D048708:Cell Growth Processes / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology
D005973:Glutamine; D018698:Glutamic Acid; D001216:Asparagine
cataplerosis; glutaminolysis; melanoma; stable isotopes