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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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