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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.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2003 Apr 11; Vol. 278 (15), pp. 12759-68. Date of Electronic Publication: 2003 Jan 29. - Publication Year :
- 2003
-
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.
- Subjects :
- Adenosine Triphosphate metabolism
Apoptosis drug effects
Apoptosis Regulatory Proteins
Breast Neoplasms
Caspase 8
Caspase 9
Cytochrome c Group metabolism
Deoxyglucose metabolism
Enzyme Activation
Female
Glucose antagonists & inhibitors
HeLa Cells
Humans
Kinetics
Lymphoma
Mitochondria physiology
Protein Processing, Post-Translational
Pyruvates metabolism
TNF-Related Apoptosis-Inducing Ligand
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha pharmacology
U937 Cells
fas Receptor physiology
Apoptosis physiology
Caspases metabolism
Enzyme Precursors metabolism
Glucose metabolism
Membrane Glycoproteins physiology
Signal Transduction physiology
Tumor Necrosis Factor-alpha physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 278
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 12556444
- Full Text :
- https://doi.org/10.1074/jbc.M212392200