title: mTORC1 inhibition in cancer cells protects from glutaminolysis-mediated apoptosis during nutrient limitation.
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.
authors.affiliation: Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux, 2 Rue Robert Escarpit, Pessac 33607, France.
authors.forename: Victor H
authors.initials: VH
authors.lastname: Villar
authors.affiliation: Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux, 2 Rue Robert Escarpit, Pessac 33607, France.
authors.forename: Tra Ly
authors.initials: TL
authors.lastname: Nguyen
authors.affiliation: Institut Bergonié, INSERM U1218, 229 Cours de l'Argonne, Bordeaux 33076, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Delcroix
authors.affiliation: Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux, 2 Rue Robert Escarpit, Pessac 33607, France.
authors.forename: Silvia
authors.initials: S
authors.lastname: Terés
authors.affiliation: Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, Université de Bordeaux, 1 Rue Camille Saint-Saëns, Bordeaux 33077, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Bouchecareilh
authors.affiliation: Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, Université de Bordeaux, 1 Rue Camille Saint-Saëns, Bordeaux 33077, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Salin
authors.affiliation: Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux, 2 Rue Robert Escarpit, Pessac 33607, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Bodineau
authors.affiliation: Institut Bergonié, INSERM U1218, 229 Cours de l'Argonne, Bordeaux 33076, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Vacher
authors.affiliation: Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, Université de Bordeaux, 1 Rue Camille Saint-Saëns, Bordeaux 33077, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Priault
authors.affiliation: Institut Bergonié, INSERM U1218, 229 Cours de l'Argonne, Bordeaux 33076, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Soubeyran
authors.affiliation: Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux, 2 Rue Robert Escarpit, Pessac 33607, France.
authors.forename: Raúl V
authors.initials: RV
authors.lastname: Durán
mesh_terms: D000906:Antibodies; D017209:Apoptosis / Q000502:physiology*; D001343:Autophagy; D045744:Cell Line, Tumor; D003470:Culture Media / Q000737:chemistry; D005786:Gene Expression Regulation / Q000502:physiology; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000037:antagonists & inhibitors*; D010957:Plasmids; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D000906:Antibodies; D003470:Culture Media; D012333:RNA, Messenger; D005973:Glutamine; D000076222:Mechanistic Target of Rapamycin Complex 1