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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Victor H. Villar & Tra Ly Nguyen & Vanessa Delcroix & Silvia Terés & Marion Bouchecareilh & Bénédicte Salin & Clément Bodineau & Pierre Vacher & Muriel Priault & Pierre Soubeyran & Raúl V. Durán, 2017. "mTORC1 inhibition in cancer cells protects from glutaminolysis-mediated apoptosis during nutrient limitation," Nature Communications, Nature, vol. 8(1), pages 1-12, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14124
    DOI: 10.1038/ncomms14124
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    Cited by:

    1. Melvin Pan & Christiane Zorbas & Maki Sugaya & Kensuke Ishiguro & Miki Kato & Miyuki Nishida & Hai-Feng Zhang & Marco M. Candeias & Akimitsu Okamoto & Takamasa Ishikawa & Tomoyoshi Soga & Hiroyuki Abu, 2022. "Glutamine deficiency in solid tumor cells confers resistance to ribosomal RNA synthesis inhibitors," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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