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 Soubeyran and Raúl V. Durán ()
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Victor H. Villar: Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux
Tra Ly Nguyen: Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux
Vanessa Delcroix: Institut Bergonié, INSERM U1218, 229 Cours de l’Argonne
Silvia Terés: Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux
Marion Bouchecareilh: Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, Université de Bordeaux
Bénédicte Salin: Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, Université de Bordeaux
Clément Bodineau: Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux
Pierre Vacher: Institut Bergonié, INSERM U1218, 229 Cours de l’Argonne
Muriel Priault: Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, Université de Bordeaux
Pierre Soubeyran: Institut Bergonié, INSERM U1218, 229 Cours de l’Argonne
Raúl V. Durán: Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract A master coordinator of cell growth, mTORC1 is activated by different metabolic inputs, particularly the metabolism of glutamine (glutaminolysis), to control a vast range of cellular processes, including autophagy. As a well-recognized tumour promoter, inhibitors of mTORC1 such as rapamycin have been approved as anti-cancer agents, but their overall outcome in patients is rather poor. Here we show that mTORC1 also presents tumour suppressor features in conditions of nutrient restrictions. Thus, the activation of mTORC1 by glutaminolysis during nutritional imbalance inhibits autophagy and induces apoptosis in cancer cells. Importantly, rapamycin treatment reactivates autophagy and prevents the mTORC1-mediated apoptosis. We also observe that the ability of mTORC1 to activate apoptosis is mediated by the adaptor protein p62. Thus, the mTORC1-mediated upregulation of p62 during nutrient imbalance induces the binding of p62 to caspase 8 and the subsequent activation of the caspase pathway. Our data highlight the role of autophagy as a survival mechanism upon rapamycin treatment.

Date: 2017
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DOI: 10.1038/ncomms14124

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