title: Glucose Deprivation Induces ATF4-Mediated Apoptosis through TRAIL Death Receptors.
abstract: Metabolic stress occurs frequently in tumors and in normal tissues undergoing transient ischemia. Nutrient deprivation triggers, among many potential cell death-inducing pathways, an endoplasmic reticulum (ER) stress response with the induction of the integrated stress response transcription factor ATF4. However, how this results in cell death remains unknown. Here we show that glucose deprivation triggered ER stress and induced the unfolded protein response transcription factors ATF4 and CHOP. This was associated with the nontranscriptional accumulation of TRAIL receptor 1 (TRAIL-R1) (DR4) and with the ATF4-mediated, CHOP-independent induction of TRAIL-R2 (DR5), suggesting that cell death in this context may involve death receptor signaling. Consistent with this, the ablation of TRAIL-R1, TRAIL-R2, FADD, Bid, and caspase-8 attenuated cell death, although the downregulation of TRAIL did not, suggesting ligand-independent activation of TRAIL receptors. These data indicate that stress triggered by glucose deprivation promotes the ATF4-dependent upregulation of TRAIL-R2/DR5 and TRAIL receptor-mediated cell death.
authors.affiliation: Cell Death Regulation Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Iurlaro
authors.affiliation: Cell Death Regulation Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Franziska
authors.initials: F
authors.lastname: Püschel
authors.affiliation: Cell Death Regulation Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Clara Lucía
authors.initials: CL
authors.lastname: León-Annicchiarico
authors.affiliation: Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin, Ireland.
authors.forename: Hazel
authors.initials: H
authors.lastname: O'Connor
authors.affiliation: Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin, Ireland.
authors.forename: Seamus J
authors.initials: SJ
authors.lastname: Martin
authors.affiliation: Cell Death Regulation Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Palou-Gramón
authors.affiliation: Cell Death Regulation Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Lucendo
authors.affiliation: Cell Death Regulation Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain cmunoz@idibell.cat.
authors.forename: Cristina
authors.identifier: http://orcid.org/0000-0002-9120-664X
authors.initials: C
authors.lastname: Muñoz-Pinedo
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D017209:Apoptosis; D059865:Endoplasmic Reticulum Stress; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000172:deficiency*; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: C497249:DDIT3 protein, human; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D005947:Glucose
keywords: ATF4; TRAIL; apoptosis; cancer metabolism; glucose