title: c-FLIP confers resistance to FAS-mediated apoptosis in anaplastic large-cell lymphoma.
abstract: We hypothesized that inhibition of the FAS-mediated apoptosis pathway by FLICE-like inhibitory protein (c-FLIP) may contribute to oncogenesis in ALK+ anaplastic large-cell lymphoma (ALCL). Treatment with increasing concentrations of CH-11 (CD95/FAS agonistic antibody) had no effect on cell viability of 2 ALK+ ALCL cell lines, Karpas 299 and SU-DHL1, each expressing high levels of c-FLIP. However, inhibition of endogenous c-FLIP expression by specific c-FLIP siRNA in Karpas 299 and SU-DHL1 cells treated with CH-11 resulted in FAS-mediated cell death associated with increased annexin V binding, apoptotic morphology, and cleavage of caspase-8. In 26 ALK+ ALCL tumors, assessed for expression of DISC-associated proteins, CD95/FAS and c-FLIP were commonly expressed, in 23 (92%) of 25 and 21 (91%) of 23 tumors, respectively. By contrast, CD95L/FASL was expressed in only 3 (12%) of 26 ALCL tumors, although it was strongly expressed by surrounding small reactive lymphocytes. Our findings suggest that overexpression of c-FLIP protects ALK+ ALCL cells from death-receptor-induced apoptosis and may contribute to ALCL pathogenesis.
authors.affiliation: Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Mauricio P
authors.initials: MP
authors.lastname: Oyarzo
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.forename: Coralyn
authors.initials: C
authors.lastname: Atwell
authors.forename: Marianna
authors.initials: M
authors.lastname: Feretzaki
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Leventaki
authors.forename: Elias
authors.initials: E
authors.lastname: Drakos
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Amin
authors.forename: George Z
authors.initials: GZ
authors.lastname: Rassidakis
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D017728:Lymphoma, Large-Cell, Anaplastic / Q000209:etiology / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D019014:fas Receptor / Q000502:physiology*
chemical_list: D017304:Annexin A5; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D019014:fas Receptor; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases