XIAP-mediated caspase inhibition in Hodgkin's lymphoma-derived B cells.
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.
Kashkar
Hamid
H
Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Goldenfelsstrasse 19-21, 50935 Cologne, Germany.
Haefs
Christiane
C
Shin
Hwain
H
Hamilton-Dutoit
Stephen J
SJ
Salvesen
Guy S
GS
Kronke
Martin
M
Jurgensmeier
Juliane M
JM
D017209:Apoptosis / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D061945:Caspase Inhibitors; D003574:Cytochrome c Group / Q000378:metabolism; D006689:Hodgkin Disease / Q000276:immunology* / Q000473:pathology; D006801:Humans; D011506:Proteins / Q000276:immunology*; D016539:Reed-Sternberg Cells / Q000276:immunology*; D014407:Tumor Cells, Cultured; D051636:X-Linked Inhibitor of Apoptosis Protein
D061945:Caspase Inhibitors; D003574:Cytochrome c Group; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human