Document Detail

Smac-mediated sensitization of human B-lymphoma cells to staurosporine- and lactacystin-triggered apoptosis is apoptosome-dependent.
MedLine Citation:
PMID:  17377587     Owner:  NLM     Status:  MEDLINE    
Second mitochondrial activator of caspase (Smac)-derived peptides have previously been shown to facilitate apoptosis of various types of cancer cells. However, it remains unclear whether the effects of such Smac agonists are dependent on apoptotic protease-activating factor-1 (Apaf-1), a key component of the apoptosome. Here, we explored the role of Apaf-1 through overexpression of this protein in the B-lymphoma cell line Raji that is defective for cytosolic Apaf-1 expression. Enforced expression of Apaf-1 rendered Raji cells sensitive to staurosporine as well as to the proteasome inhibitor, lactacystin. Importantly, co-treatment with Smac peptides resulted in a threefold higher degree of apoptosis in Apaf-1-expressing Raji cells, but not in mock-transfected cells. Smac peptides also potentiated apoptosis of the DG-75 cell line following liberation of endogenous Apaf-1 from the plasma membrane, but were ineffective when added alone. Furthermore, we observed high levels of expression in several B-lymphoma cell lines of cellular inhibitor of apoptosis protein-2 (cIAP2), and immunodepletion of cIAP2 (a target of Smac) was found to sensitize Apaf-1-overexpressing Raji cells to cytochrome c-dependent caspase activation. Collectively, these results demonstrate the importance of Apaf-1 in Smac-mediated potentiation of apoptosis of B-lymphoma-derived cells.
Y Sun; A Ottosson; S Pervaiz; B Fadeel
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-03-22
Journal Detail:
Title:  Leukemia     Volume:  21     ISSN:  0887-6924     ISO Abbreviation:  Leukemia     Publication Date:  2007 May 
Date Detail:
Created Date:  2007-04-25     Completed Date:  2007-06-04     Revised Date:  2013-03-04    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  England    
Other Details:
Languages:  eng     Pagination:  1035-43     Citation Subset:  IM    
Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
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MeSH Terms
Acetylcysteine / analogs & derivatives*,  pharmacology
Apoptosis / drug effects*
Apoptosomes / physiology*
Apoptotic Protease-Activating Factor 1 / physiology
Caspases / metabolism
Cell Line, Tumor
Inhibitor of Apoptosis Proteins / analysis
Intracellular Signaling Peptides and Proteins / physiology*
Lymphoma, B-Cell / drug therapy,  pathology*
Membrane Microdomains / physiology
Mitochondrial Proteins / physiology*
Staurosporine / pharmacology*
Reg. No./Substance:
0/APAF1 protein, human; 0/Apoptosomes; 0/Apoptotic Protease-Activating Factor 1; 0/BIRC3 protein, human; 0/DIABLO protein, human; 0/Inhibitor of Apoptosis Proteins; 0/Intracellular Signaling Peptides and Proteins; 0/Mitochondrial Proteins; 133343-34-7/lactacystin; 616-91-1/Acetylcysteine; 62996-74-1/Staurosporine; EC 3.4.22.-/Caspases

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