[cFLIP diminishes CD95-induced apoptosis of CD30-stimulated cutaneous anaplastic large T cell lymphoma (cALCL) cells].
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.
Hirsch
B
B
Institut für Pathologie, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin. burkhard.hirsch@charite.de
Braun
F K
FK
Al-Yacoub
N
N
Assaf
C
C
Kadin
M E
ME
Sterry
W
W
Eberle
J
J
Dürkop
H
H
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*
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
Oncogene. 2001 Feb 1;20(5):590-8
11313991
J Biol Chem. 2002 Nov 22;277(47):45162-71
12215447
Blood. 2005 Sep 1;106(5):1839-42
15878978
Curr Hematol Malig Rep. 2010 Jul;5(3):140-7
20446121
Curr Opin Immunol. 1999 Jun;11(3):277-85
10375553
Nat Genet. 2003 Mar;33(3):401-6
12590264
Int J Biochem Cell Biol. 2010 Feb;42(2):210-3
19932761
Semin Immunol. 2003 Jun;15(3):145-57
14563113
Am J Pathol. 2008 Feb;172(2):510-20
18187570
Blood. 2008 Feb 15;111(4):1848-54
18079362
Blood. 1985 Oct;66(4):848-58
3876124
J Invest Dermatol. 2010 Mar;130(3):826-40
19890350
J Exp Med. 2004 Apr 19;199(8):1041-52
15078899
Curr Drug Targets. 2009 Feb;10(2):110-7
19199906
FASEB J. 2009 Jun;23(6):1625-37
19141537