mTORC1 inhibition in cancer cells protects from glutaminolysis-mediated apoptosis during nutrient limitation


mTORC1 inhibition in cancer cells protects from glutaminolysis-mediated apoptosis during nutrient limitation

Victor H. Villar, Tra Ly Nguyen, Vanessa Delcroix, Silvia Terés, Marion Bouchecareilh, Bénédicte Salin, Clément Bodineau, Pierre Vacher, Muriel Priault, Pierre Soubeyran2 and Raúl V. Durán (2017) mTORC1 inhibition in cancer cells protects from glutaminolysis-mediated apoptosis during nutrient limitation. Nature Comm. 8, 14124.

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The Group of Metabolism and Cell Signaling, led by Raul V. Duran, is an emerging group that has been incorporated in 2013 into the Institut Européen de Chimie et Biologie (IECB, Pessac), affiliated to the U1218 Unit (INSERM, Institut Bergonié, Bordeaux). The principal aim of our group is to provide fundamental insight in the mechanisms by which cell signaling, and in particular mTOR pathway as a central regulator for cell growth, responds to nutrients and how these regulatory mechanisms are deregulated in cancer. For this purpose, we develop a multidisciplinary approach, involving biochemical cell signaling analysis, structure/function relationship of proteins, enzymology and physiology, proteomics and metabolomics.

Glutamine is the most abundant amino acid in the blood and a nitrogen source for cells. This amino acid has been described as a crucial nutrient for tumour proliferation, and indeed a vast number of different types of tumour cells consume abnormally high quantities of glutamine and develop glutamine addiction. Glutamine is mostly degraded in the cell through glutaminolysis. Glutaminolysis comprises two-step enzymatic reactions, whereby glutamine is first deamidated to glutamate, in a reaction catalysed by glutaminase (GLS), and then glutamate is deaminated to a-ketoglutarate (aKG), in a reaction catalysed by glutamate dehydrogenase. In addition, leucine, another important amino acid from a signalling point of view, activates allosterically glutamate dehydrogenase and promotes the production of glutaminolitic aKG. Therefore, leucine and glutamine cooperate to produce aKG, an intermediate of the tricarboxylic acid cycle. Besides this anaplerotic role of glutamine, glutaminolysis also activates mTORC1 pathway and inhibits autophagy.

The results presented in our publication propose a complete molecular mechanism to explain how the activation of glutaminolysis in the absence of other amino acids induces an unbalanced activation of mTORC1 and the subsequent inhibition of autophagy, which promotes apoptosis upon amino acid deprivation. This unprecedented function of both glutamine metabolism and mTORC1 (two well-known pro-proliferative inducers) as activators of cell death in tumour cells place both elements with a potential tumour suppressor functionality that could be exploited in therapy. We observed that the addition of glutamine and leucine at similar concentrations than used in a complete culture medium to amino acid-starved cells (what we called ‘LQ treatment’) promoted the activation of apoptotic cell death through glutaminolysis, as the inhibition of this process abrogated this cell death induction. The unexpected role of glutaminolysis as a cell death inducing mechanism during nutrient restriction also pointed at the importance of nutritional balance in the control of cancer cell viability and the potential use of this metabolic disequilibrium to identify new metabolic addictions.

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