Priority Research Papers:

Glutamate and asparagine cataplerosis underlie glutamine addiction in melanoma

Boris Ratnikov _, Pedro Aza-Blanc, Ze’ev A. Ronai, Jeffrey W. Smith, Andrei L. Osterman and David A. Scott

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Oncotarget. 2015; 6:7379-7389. https://doi.org/10.18632/oncotarget.3132

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Boris Ratnikov1, Pedro Aza-Blanc1, Ze’ev A. Ronai1, Jeffrey W. Smith1, Andrei L. Osterman1, David A. Scott1

1Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA

Correspondence to:

Andrei L. Osterman, e-mail: [email protected]

Jeffrey W. Smith, e-mail: [email protected]

Keywords: Melanoma, Glutaminolysis, Cataplerosis, Stable isotopes

Received: January 09, 2015     Accepted: January 09, 2015     Published: February 28, 2015


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.

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