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Updated: Aug 11, 2026
Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation
Published on: March 5, 2018
The proteasome is required for rapid initiation of death receptor-induced apoptosis
Dennis Sohn1, Gudrun Totzke, Frank Essmann
1Institute of Molecular Medicine, University of Düsseldorf, Building 23.12, Universitätsstrasse 1, D-40225 Düsseldorf, Germany.
Abstract:
Due to their tremendous apoptosis-inducing potential, proteasomal inhibitors (PIs) have recently entered clinical trials. Here we show, however, that various PIs rescued proliferating tumor cells from death receptor-induced apoptosis. This protection correlated with the stabilization of X-linked IAP (XIAP) and c-FLIP and the inhibition of caspase activation. Together with the observation that PIs could not protect cells expressing XIAP or c-FLIP short interfering RNAs (siRNAs) from death receptor-induced apoptosis, our results demonstrate that PIs mediate their protective effect via the stabilization of these antiapoptotic proteins. Furthermore, we show that once these proteins were eliminated, either by long-term treatment with death receptor ligands or by siRNA-mediated suppression, active caspases accumulated to an even larger extent in the presence of PIs. Together, our data support a biphasic role for the proteasome in apoptosis, as they show that its constitutive activity is crucial for the rapid initiation of the death program by eliminating antiapoptotic proteins, whereas at later stages, the proteasome acts in an antiapoptotic manner due to the proteolysis of caspases. Thus, for a successful PI-based tumor therapy, it is crucial to carefully evaluate basal proteasomal activity and the status of antiapoptotic proteins, as their PI-mediated prolonged stability might even cause adverse effects, leading to the survival of a tumor.
Insights
Proteasomal inhibitors (PIs) can paradoxically protect tumor cells from apoptosis by stabilizing antiapoptotic proteins like XIAP and c-FLIP. This highlights a biphasic role for proteasomes in apoptosis, crucial for effective cancer therapy.
Area of Science:
- Cellular Biology
- Cancer Research
- Molecular Medicine
Background:
- Proteasomal inhibitors (PIs) are emerging as a promising cancer therapy due to their apoptosis-inducing potential.
- The precise mechanisms by which PIs affect cancer cell survival, particularly in response to death receptor signaling, require further elucidation.
Purpose of the Study:
- To investigate the role of proteasomal inhibitors (PIs) in regulating apoptosis induced by death receptors in proliferating tumor cells.
- To elucidate the molecular mechanisms underlying the protective effects of PIs against death receptor-mediated apoptosis.
Main Methods:
- Treatment of proliferating tumor cells with various proteasomal inhibitors (PIs).
- Assessment of apoptosis induction via death receptor pathways.
- Analysis of the expression levels of X-linked inhibitor of apoptosis protein (XIAP) and cellular FLICE-inhibitory protein (c-FLIP).
- Utilized short interfering RNAs (siRNAs) to suppress XIAP and c-FLIP expression.
- Monitored caspase activation and proteasome activity.
Main Results:
- Proteasomal inhibitors (PIs) were found to rescue proliferating tumor cells from death receptor-induced apoptosis.
- This protection was associated with the stabilization of antiapoptotic proteins, specifically X-linked IAP (XIAP) and c-FLIP.
- PIs inhibited caspase activation, and this effect was dependent on the presence of XIAP and c-FLIP.
- Elimination of XIAP or c-FLIP abrogated the protective effect of PIs.
- Under conditions of prolonged death ligand treatment or siRNA-mediated suppression, PIs led to increased accumulation of active caspases.
- Data suggest a biphasic role for the proteasome in apoptosis: crucial for initiating apoptosis by degrading antiapoptotic proteins early on, and acting anti-apoptotically later by degrading caspases.
Conclusions:
- Proteasomal inhibitors (PIs) can unexpectedly promote tumor cell survival by stabilizing XIAP and c-FLIP, thereby inhibiting apoptosis.
- The proteasome plays a dual role in apoptosis, influencing both the initiation and execution phases.
- Careful evaluation of basal proteasomal activity and antiapoptotic protein levels is essential for optimizing PI-based cancer therapies to avoid potential adverse effects like tumor survival.
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