The Journal of Experimental Medicine
Avanti Polar Lipids
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Published 21 July 2003. doi:10.1084/jem.20021279
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© Rockefeller University Press, 0022-1007/2003/7/341 $5.00
The Journal of Experimental Medicine, Volume 198, Number 2, 341-347

XIAP-mediated Caspase Inhibition in Hodgkin's Lymphoma–derived B Cells

Hamid Kashkar1, Christiane Haefs1, Hwain Shin2, Stephen J. Hamilton-Dutoit3, Guy S. Salvesen2, Martin Krönke1 and Juliane M. Jürgensmeier1

1 Institute for Medical Microbiology, Immunology, and Hygiene, University of Cologne, 50935 Köln, Germany
2 The Burnham Institute, Program for Apoptosis and Cell Death Research, La Jolla, CA 92037
3 Institute of Pathology, Aarhus University Hospital, Komunehospitalet, 8000 Aarhus C, Denmark

Address correspondence to Martin Krönke, Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Goldenfelsstrasse 19-21, 50935 Cologne, Germany. Phone: 49-221-478-3060; Fax: 49-221-478-3067; E-mail: martin.kroenke{at}medizin.uni-koeln.de

The malignant Hodgkin and Reed-Sternberg cells of Hodgkin's lymphoma (HL) and HL-derived B cell lines were previously shown to be resistant to different apoptotic stimuli. We show here that cytochrome c fails to stimulate caspases-9 and -3 activation in cytosolic extracts of HL-derived B cells, which is due to high level expression of X-linked inhibitor of apoptosis (XIAP). Coimmunoprecipitation studies revealed that XIAP, apoptosis protease-activating factor–1, and caspase-3 are complexed in HL-derived B cell lysates. Even after stimulation with exogenous cytochrome c and dATP, XIAP impairs the proteolytic processing and activation of caspase-3. In cytosolic extracts, inhibition of XIAP by the second mitochondria-derived activator of caspases (Smac)/DIABLO, or immunodepletion of XIAP restores cytochrome c–triggered processing and activation of caspase-3. Smac or a Smac-derived agonistic peptide also sensitized intact HL-derived B cells for the apoptotic action of staurosporine. Finally, Hodgkin and Reed-Sternberg cells of primary tumor HL tissues also constitutively and abundantly express XIAP. The results of this paper suggest that high level XIAP expression is a hallmark of HL, which may play a crucial role in resistance to apoptosis.

Key Words: cancer • tumor • apoptosis • mitochondria • Smac/DIABLO


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