title: [cFLIP diminishes CD95-induced apoptosis of CD30-stimulated cutaneous anaplastic large T cell lymphoma (cALCL) cells].
abstract: Stimulation of the TNF receptors CD30 and CD95 exerts opposite effects. Crosstalk of both receptors is unknown. We aimed to reveal regulatory mechanisms of CD30-induced effects on CD95 signaling of cALCL cell lines. "CD30/CD95 crosstalk analysis" was performed in cALCL cell lines by comparison of CD30 or CD95 stimulation and CD30/CD95 costimulation. Receptor expression and induction of apoptosis was investigated by flow cytometry. mRNA expression of CD30-inducible genes (cFLIP, TRAF1, cIAP2, and A20) was compared by semiquantitative reverse transcription (RT-RQ-) PCR in stimulated and unstimulated cells. Protein expression of IκBα, p100/p52, caspase-8, caspase-3, and cFLIP was analyzed by immunoblotting. A lentiviral-based shRNA-mediated approach was used to inhibit cFLIP expression. CD30/CD95 crosstalk experiments revealed that CD30 ligation leads to NFκB-mediated cFLIP upregulation in cALCL cells, which in turn enhanced resistance to CD95-mediated apoptosis. This effect is based on the CD30-induced upregulation of cFLIP. Knockdown of cFLIP restores sensitivity to CD95-mediated apoptosis. We conclude that the anti-apoptotic function of CD30 antibodies should be kept in mind if CD30 antibody-based therapeutic concepts for ALCL lymphoma are considered.
authors.affiliation: Institut für Pathologie, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin. burkhard.hirsch@charite.de
authors.forename: B
authors.initials: B
authors.lastname: Hirsch
authors.forename: F K
authors.initials: FK
authors.lastname: Braun
authors.forename: N
authors.initials: N
authors.lastname: Al-Yacoub
authors.forename: C
authors.initials: C
authors.lastname: Assaf
authors.forename: M E
authors.initials: ME
authors.lastname: Kadin
authors.forename: W
authors.initials: W
authors.lastname: Sterry
authors.forename: J
authors.initials: J
authors.lastname: Eberle
authors.forename: H
authors.initials: H
authors.lastname: Dürkop
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D017730:Ki-1 Antigen / Q000235:genetics*; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics* / Q000473:pathology*; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D020239:Receptor Cross-Talk; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology*; D015854:Up-Regulation / Q000235:genetics; D019014:fas Receptor / Q000235:genetics*
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C491901:FAS protein, human; D017730:Ki-1 Antigen; D012333:RNA, Messenger; D019014:fas Receptor
references.citation: Oncogene. 2001 Feb 1;20(5):590-8
references.pmid: 11313991
references.citation: J Biol Chem. 2002 Nov 22;277(47):45162-71
references.pmid: 12215447
references.citation: Blood. 2005 Sep 1;106(5):1839-42
references.pmid: 15878978
references.citation: Curr Hematol Malig Rep. 2010 Jul;5(3):140-7
references.pmid: 20446121
references.citation: Curr Opin Immunol. 1999 Jun;11(3):277-85
references.pmid: 10375553
references.citation: Nat Genet. 2003 Mar;33(3):401-6
references.pmid: 12590264
references.citation: Int J Biochem Cell Biol. 2010 Feb;42(2):210-3
references.pmid: 19932761
references.citation: Semin Immunol. 2003 Jun;15(3):145-57
references.pmid: 14563113
references.citation: Am J Pathol. 2008 Feb;172(2):510-20
references.pmid: 18187570
references.citation: Blood. 2008 Feb 15;111(4):1848-54
references.pmid: 18079362
references.citation: Blood. 1985 Oct;66(4):848-58
references.pmid: 3876124
references.citation: J Invest Dermatol. 2010 Mar;130(3):826-40
references.pmid: 19890350
references.citation: J Exp Med. 2004 Apr 19;199(8):1041-52
references.pmid: 15078899
references.citation: Curr Drug Targets. 2009 Feb;10(2):110-7
references.pmid: 19199906
references.citation: FASEB J. 2009 Jun;23(6):1625-37
references.pmid: 19141537