Cisplatin (CDDP) sensitizes human osteosarcoma cell to Fas/CD95-mediated apoptosis by down-regulating FLIP-L expression.
The mechanisms of escape from Fas/CD95-mediated apoptosis induced by immunosurveillance(NK cells and T cells) in tumor cells are correlated to tumorigenicity. Human osteosarcoma cell MG-63 constitutively expressed cell surface Fas antigen but was resistant to apoptosis by Fas stimulation. However, suboptimal dose of cisplatin(CDDP) could sensitize MG-63 cells to Fas-mediated apoptosis without up-regulation of cell-surface Fas antigen. Western blotting analysis showed that MG-63 cells constitutively expressed FLICE inhibitory protein long form(FLIP-L), which was a novel anti-apoptotic protein and had a potency of tumorigenicity. CDDP down-regulated FLIP-L in a time-dependent manner in MG-63 cells but did not influence expression of other anti-apoptotic molecules such as XIAP, c-IAP-1, c-IAP-2, FADD or pro-caspase-8. Moreover, antisense oligonucleotide to FLIP-L confirmed that down-regulation of FLIP-L induced sensitization to Fas-mediated apoptosis. These findings suggest that FLIP-L contributes to resistance to Fas-mediated apoptosis in MG-63 cells, and sensitization to Fas-mediated apoptosis by CDDP can be a new application of immune therapy.
Kinoshita
H
H
Department of Orthopeadic Surgery, Yamanashi Medical University, Yamanashi, Japan.
Yoshikawa
H
H
Shiiki
K
K
Hamada
Y
Y
Nakajima
Y
Y
Tasaka
K
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation; D004792:Enzyme Precursors / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins / Q000187:drug effects* / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012516:Osteosarcoma / Q000378:metabolism / Q000628:therapy*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D019014:fas Receptor / Q000378:metabolism / Q000494:pharmacology*
D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D019014:fas Receptor; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D002945:Cisplatin