Resistance of cutaneous anaplastic large-cell lymphoma cells to apoptosis by death ligands is enhanced by CD30-mediated overexpression of c-FLIP.
Death ligands, including TNF-alpha, CD95L/FasL, and TRAIL, mediate safeguard mechanisms against tumor growth and critically contribute to lymphocyte homeostasis. We investigated death receptor-mediated apoptosis and CD30/CD95 crosstalk in four CD30-positive cell lines of cutaneous anaplastic large-cell lymphoma (cALCL). Whereas CD95 stimulation strongly induced apoptosis in cALCL cells, the pro-apoptotic pathways of TNF-alpha and TRAIL were completely blocked at an early step. Expression of TNF receptor 1 was lost in three of four cell lines, providing an explanation for TNF-alpha unresponsiveness. TRAIL resistance may be explained by the consistent overexpression of cellular flice inhibitory protein (c-FLIP) (four of four cell lines) and frequent loss of the pro-apoptotic Bcl-2 protein Bid (three of four cell lines). Changes at the receptor-expression level were largely ruled out. CD30/CD95 crosstalk experiments showed that CD30 ligation leads to NF-kappaB-mediated c-FLIP upregulation in cALCL cells, which in turn conferred enhanced resistance to CD95-mediated apoptosis. Knockdown of c-FLIP by a lentiviral approach enhanced basic apoptosis rates in cALCL cells and diminished the CD30-mediated suppression of apoptosis, thus proving the significance of c-FLIP in this context. These in vitro findings may be indicative of the clinical situation of cALCL. Further clarifying the defects in apoptosis pathways in cutaneous lymphomas may lead to improved therapies for these disorders.
Braun
Frank K
FK
Department of Dermatology and Allergy, Charité-University Medical Center Berlin, HTCC-Skin Cancer Center, Berlin, Germany.
Hirsch
Burkhard
B
Al-Yacoub
Nadya
N
Dürkop
Horst
H
Assaf
Chalid
C
Kadin
Marshall E
ME
Sterry
Wolfram
W
Eberle
Jürgen
J
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics* / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D017730:Ki-1 Antigen / Q000378:metabolism* / Q000494:pharmacology; D017728:Lymphoma, Large-Cell, Anaplastic / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D020239:Receptor Cross-Talk / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D019014:fas Receptor / Q000378:metabolism
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D017730:Ki-1 Antigen; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D019014:fas Receptor; D020169:Caspases