Laussmann, M. A., Passante, Egle, Hellwig, C. T., Tomiczek, B., Flanagan, L., Prehn, J. H. M., Huber, H. J. and Rehm, M. (2012) Proteasome Inhibition Can Impair Caspase-8 Activation upon Submaximal Stimulation of Apoptotic Tumor Necrosis Factor-related Apoptosis Inducing Ligand (TRAIL) Signaling. Journal of Biological Chemistry, 287 (18). pp. 14402-14411. ISSN 0021-9258
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Official URL: http://dx.doi.org/10.1074/jbc.M111.304378
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.
|Uncontrolled Keywords (separate with ;):||Apoptotic; Bortezomib; Caspases; Cervical cancer cells; Current models; Death-inducing signaling complexes; Modeling results; Proteasome inhibitors; Proteasomes; Protein level; Relative abundance; Signaling proteins; Single cells; Time-lapse imaging; Tumor necrosis|
|Subjects:||B - Subjects allied to medicine > B230 - Pharmacy|
|Schools:||Faculty of Clinical & Biomedical Sciences > School of Pharmacy and Biomedical Sciences|
|Deposited By:||Simone Finley|
|Deposited On:||15 Feb 2013 12:37|
|Last Modified:||09 Aug 2016 15:17|
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