Proteasome Inhibition Can Impair Caspase-8 Activation upon Submaximal Stimulation of Apoptotic Tumor Necrosis Factor-related Apoptosis Inducing Ligand (TRAIL) Signaling

作者：Laussmann Maike A; Passante Egle; Hellwig Christian T; Tomiczek Bartlomiej; Flanagan Lorna; Prehn Jochen H M; Huber Heinrich J; Rehm Markus^*

来源：Journal of Biological Chemistry, 2012, 287(18): 14402-14411.

DOI：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 pro-survival 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 pro-survival 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.

• 出版日期2012-4-27