Document Detail


Interferon-gamma sensitizes osteosarcoma cells to Fas-induced apoptosis by up-regulating Fas receptors and caspase-8.
MedLine Citation:
PMID:  15390286     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Osteosarcoma is the third most frequent neoplasm in adolescents. Although chemotherapy, frequently used in pre- and post-operative settings, has resulted in significant improvement in disease-free survival, some patients show little sensitivity to chemotherapy and alternative therapeutic strategies are needed. Because the Fas ligand/Fas receptor (CD95, APO-1) apoptosis pathway is a potential therapeutic target in osteosarcomas, we examined the effect of IFN-gamma on Fas-induced apoptosis in four osteosarcoma cell lines. PROCEDURE AND RESULTS: As measured by flow cytometry, all cell lines expressed cell surface IFN-gamma receptors, and when cultured for 2 days in the presence of IFN-gamma, all cell lines exhibited a significant increase in expression of Fas receptors. By flow cytometric detection of intracellular fragmented DNA as a marker of apoptosis, all cell lines cultured with either IFN-gamma or anti-Fas antibody (clone CH-11) alone showed only moderate apoptosis, whereas significantly high levels of apoptosis occurred in cells cultured with both IFN-gamma and CH-11. Western blotting analysis also revealed that IFN-gamma caused up-regulation of caspase-8 in all cell lines, but no change in Fas-associated death domain protein (FADD/MORT1) or caspase-3. Both caspase-8 and caspase-3 were activated when apoptosis was induced with both IFN-gamma and CH-11. Addition to cultures of z-IETD-fmk, an inhibitor of caspase-8, significantly blocked this apoptosis. CONCLUSIONS: IFN-gamma sensitizes osteosarcoma cells to Fas-induced apoptosis through up-regulation of Fas receptor and caspase-8. Combined immunotherapy with IFN-gamma and either anti-Fas monoclonal antibody or cytotoxic T cells that bear Fas ligand might be a useful adjunctive therapy for patients with osteosarcoma.
Authors:
Hiroto Inaba; Maria Glibetic; Steven Buck; Yaddanapudi Ravindranath; Joseph Kaplan
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Pediatric blood & cancer     Volume:  43     ISSN:  1545-5009     ISO Abbreviation:  Pediatr Blood Cancer     Publication Date:  2004 Dec 
Date Detail:
Created Date:  2004-11-03     Completed Date:  2005-01-18     Revised Date:  2009-01-12    
Medline Journal Info:
Nlm Unique ID:  101186624     Medline TA:  Pediatr Blood Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  729-36     Citation Subset:  IM    
Copyright Information:
2004 Wiley-Liss, Inc.
Affiliation:
Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, Michigan, USA. hiroto.inaba@stjude.org
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing / analysis
Antigens, CD95 / genetics*,  physiology
Apoptosis / drug effects*
Caspase 3
Caspase 8
Caspases / analysis,  genetics*
Cell Line, Tumor
Drug Synergism
Fas-Associated Death Domain Protein
Flow Cytometry
Humans
Interferon-gamma / pharmacology*
Osteosarcoma / pathology*
Up-Regulation / drug effects
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Antigens, CD95; 0/FADD protein, human; 0/Fas-Associated Death Domain Protein; 82115-62-6/Interferon-gamma; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/CASP8 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 8; EC 3.4.22.-/Caspases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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