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Molecular and Cellular Biology, February 2003, p. 777-790, Vol. 23, No. 3
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.3.777-790.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Proteasome Inhibition Results in TRAIL Sensitization of Primary Keratinocytes by Removing the Resistance-Mediating Block of Effector Caspase Maturation{dagger}

Martin Leverkus,1* Martin R. Sprick,2 Tina Wachter,1 Thilo Mengling,1 Bernd Baumann,3 Edgar Serfling,4 Eva-B. Bröcker,1 Matthias Goebeler,1 Manfred Neumann,4 and Henning Walczak2

Department of Dermatology,1 Institute of Pathology, University of Würzburg Medical School, 97080 Würzburg,4 Division of Apoptosis Regulation, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg,2 Department of Physiological Chemistry, University of Ulm, 89081 Ulm, Germany3

Received 22 May 2002/ Returned for modification 18 July 2002/ Accepted 6 November 2002

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exerts potent cytotoxic activity against transformed keratinocytes, whereas primary keratinocytes are relatively resistant. In several cell types, inhibition of the proteasome sensitizes for TRAIL-induced apoptosis by interference with NF-{kappa}B activation. Here we describe a novel intracellular mechanism of TRAIL resistance in primary cells and how this resistance is removed by proteasome inhibitors independent of NF-{kappa}B in primary human keratinocytes. This sensitization was not mediated at the receptor-proximal level of TRAIL DISC formation or caspase 8 activation but further downstream. Activation of caspase 3 was critical, as it only occurred when mitochondrial apoptotic pathways were activated, as reflected by Smac/DIABLO, HtrA2, and cytochrome c release. Smac/DIABLO and HtrA2 are needed to release the X-linked inhibitor-of-apoptosis protein (XIAP)-mediated block of full caspase 3 maturation. XIAP can effectively block caspase 3 maturation and, intriguingly, is highly expressed in primary but not in transformed keratinocytes. Ectopic XIAP expression in transformed keratinocytes resulted in increased resistance to TRAIL. Our data suggest that breaking of this resistance via proteasome inhibitors, which are potential anticancer drugs, may sensitize certain primary cells to TRAIL-induced apoptosis and could thereby complicate the clinical applicability of a combination of TRAIL receptor agonists with proteasome inhibitors.

* Corresponding author. Mailing address: Department of Dermatology, University of Würzburg Medical School, Josef-Schneider-Str. 2, 97080 Würzburg, Germany. Phone: 49 931 201 26356. Fax: 49 931 201 26700. E-mail: leverkus_m{at}klinik.uni-wuerzburg.de.

{dagger} This article is dedicated to Harald zur Hansen on the occasion of his retirement as head of the German Cancer Research Center (Deutsches Krebs forschungszentrum) in Heidelberg with gratitude and appreciation for 20 years of leadership.

Molecular and Cellular Biology, February 2003, p. 777-790, Vol. 23, No. 3
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.3.777-790.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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