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The Proteasome Is Required for Rapid Initiation of Death Receptor-Induced Apoptosis

Dennis Sohn,^1, Gudrun Totzke,^1, Frank Essmann,¹ Klaus Schulze-Osthoff,¹ Bodo Levkau,² and Reiner U. Jänicke^1*

University of Düsseldorf, Institute of Molecular Medicine, Universitätsstrasse 1, 40225 Düsseldorf, Germany,¹ University of Essen, Institute of Pathophysiology, Hufelandstrasse 55, 45112 Essen, Germany²

Received 20 October 2005/ Returned for modification 17 November 2005/ Accepted 6 December 2005

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.

Both authors contributed equally to this work.

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