Proteasome Inhibition Can Impair Caspase-8 Activation upon Submaximal Stimulation of Apoptotic Tumor Necrosis Factor-related Apoptosis Inducing Ligand (TRAIL) Signaling*
| Autor: | Markus Rehm, Jochen H. M. Prehn, Lorna Flanagan, Maike A. Laussmann, Bartłomiej Tomiczek, Christian T. Hellwig, Heinrich J. Huber, Egle Passante |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Programmed cell death
Proteasome Endopeptidase Complex Antineoplastic Agents Apoptosis Caspase 8 Biochemistry Bortezomib TNF-Related Apoptosis-Inducing Ligand 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Epoxomicin medicine Humans Protease Inhibitors Molecular Biology Caspase 030304 developmental biology 0303 health sciences biology fungi food and beverages Cell Biology Boronic Acids 3. Good health Cell biology Enzyme Activation chemistry Proteasome 030220 oncology & carcinogenesis Pyrazines biology.protein Signal transduction Oligopeptides Proteasome Inhibitors medicine.drug Signal Transduction HeLa Cells |
| Zdroj: | Journal of Biological Chemistry; Vol 287 Journal of Biological Chemistry |
| Popis: | Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) can induce extrinsic apoptosis, resulting in caspase-8 activation, but may also initiate transcription-dependent prosurvival signaling. Proteasome inhibitors were suggested to promote TRAIL signal transduction through the death-inducing signaling complex (DISC) by modulating the relative abundance of core DISC components, thereby enhancing caspase-8 activation and apoptosis. To test this hypothesis, we quantified the changes in DISC protein levels as an early consequence of proteasome inhibition in HeLa cervical cancer cells and, based on these data, mathematically modeled the proapoptotic TRAIL signaling toward caspase-8 activation. Modeling results surprisingly suggested that caspase-8 activation might be delayed in presence of proteasome inhibitors, in particular at submaximal TRAIL doses. Subsequent FRET-based single cell time-lapse imaging at conditions where transcription dependent prosurvival signaling was blocked confirmed this hypothesis: caspase-8 activity was delayed by hours in the presence of proteasome inhibitors epoxomicin or bortezomib. Corresponding delays were detected for effector caspase processing and cell death. Contrary to current models, we therefore provide evidence that synergies between TRAIL and proteasome inhibitors do not result from changes in the levels of core DISC signaling proteins. |
| Databáze: | OpenAIRE |
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