title: Inhibition of glucose metabolism sensitizes tumor cells to death receptor-triggered apoptosis through enhancement of death-inducing signaling complex formation and apical procaspase-8 processing.
abstract: Tumors display a high rate of glucose uptake and glycolysis. We investigated how inhibition of glucose metabolism could affect death receptor-mediated apoptosis in human tumor cells of diverse origin. We show that both substitution of glucose for pyruvate and treatment with 2-deoxyglucose enhanced apoptosis induced by tumor necrosis factor (TNF)-alpha, CD95 agonistic antibody, and TNF-related apoptosis-inducing ligand (TRAIL). Inhibition of glucose metabolism enhanced killing of myeloid leukemia U937, cervical carcinoma HeLa, and breast carcinoma MCF-7 cells upon death receptor ligation. Caspase activation, mitochondrial depolarization, and cytochrome c release were increased under these conditions. Glucose deprivation-mediated sensitization to apoptosis was prevented in MCF-7 cells overexpressing BCL-2. Interestingly, the human B-lymphoblastoid cell line SKW6.4, a prototype for mitochondria-independent death receptor-induced apoptosis, was also sensitized to anti-CD95 and TRAIL-induced apoptosis under glucose-free conditions. Changes in c-FLIP(L) and cFLIPs levels were observed in some but not all the cell lines studied following glucose deprivation. Glucose deprivation enhanced death receptor-triggered formation of death-inducing signaling complex and early processing of procaspase-8. Altogether, these results suggest that the glycolytic pathway may be an important target for therapeutic intervention to sensitize tumor cells to selectively toxic soluble death ligands or death ligand-expressing cells of the immune system by facilitating the activation of initiator caspase-8.
authors.affiliation: Instituto de Parasitologia y Biomedicina, Consejo Superior de Investigaciones Cientificas, Calle Ventanilla 11, 18001 Granada, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Muñoz-Pinedo
authors.forename: Carmen
authors.initials: C
authors.lastname: Ruiz-Ruiz
authors.forename: Carmen
authors.initials: C
authors.lastname: Ruiz de Almodóvar
authors.forename: Carmen
authors.initials: C
authors.lastname: Palacios
authors.forename: Abelardo
authors.initials: A
authors.lastname: López-Rivas
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D003574:Cytochrome c Group / Q000378:metabolism; D003847:Deoxyglucose / Q000378:metabolism; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008223:Lymphoma; D008562:Membrane Glycoproteins / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology; D011499:Protein Processing, Post-Translational; D011773:Pyruvates / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*; D020298:U937 Cells; D019014:fas Receptor / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D003574:Cytochrome c Group; D004792:Enzyme Precursors; D008562:Membrane Glycoproteins; D011773:Pyruvates; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D005947:Glucose