Abstract
Intracellular CD95/Fas-signaling pathways have not been investigated in melanoma yet. Two different CD95 receptor-induced apoptotic pathways are presently known in other cell types: (i) direct activation of caspase-8 and (ii) induction of ceramide-mediated mitochondrial activation, both leading to subsequent caspase-3 activation. In the present study, five of 11 melanoma cell populations were shown to release cytochrome c from mitochondria, which activates caspase-3 and finally results in DNA fragmentation upon treatment with the agonistic monoclonal antibody CH-11. In contrast, this apoptotic pathway was not activated in the remaining six melanoma cell populations. Interestingly, the susceptibility of melanoma cells to CD95L/FasL-triggered cell death was clearly correlated with N-acetylsphingosine-mediated apoptosis. Our results are in line with a defect upstream of mitochondrial cytochrome c release in resistant cells.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing*
-
Antibodies, Monoclonal / immunology
-
Antibodies, Monoclonal / pharmacology
-
Apoptosis / drug effects*
-
Carrier Proteins / genetics
-
Caspase 3
-
Caspase 8
-
Caspase 9
-
Caspases / genetics
-
Caspases / metabolism
-
Cytochrome c Group / metabolism*
-
DNA Fragmentation / drug effects
-
Drug Resistance, Neoplasm
-
Enzyme Activation / drug effects
-
Fas Ligand Protein
-
Fas-Associated Death Domain Protein
-
Gene Expression
-
Humans
-
Hydrolysis / drug effects
-
Melanoma / enzymology
-
Melanoma / genetics
-
Melanoma / metabolism
-
Melanoma / pathology*
-
Membrane Glycoproteins / genetics
-
Mitochondria / drug effects
-
Mitochondria / metabolism*
-
RNA, Messenger / analysis
-
RNA, Messenger / genetics
-
Signal Transduction / drug effects
-
Sphingomyelins / metabolism
-
Sphingosine / analogs & derivatives*
-
Sphingosine / pharmacology
-
Tumor Cells, Cultured
-
fas Receptor / genetics
-
fas Receptor / immunology
-
fas Receptor / physiology*
Substances
-
Adaptor Proteins, Signal Transducing
-
Antibodies, Monoclonal
-
Carrier Proteins
-
Cytochrome c Group
-
FADD protein, human
-
FASLG protein, human
-
Fas Ligand Protein
-
Fas-Associated Death Domain Protein
-
Membrane Glycoproteins
-
N-acetylsphingosine
-
RNA, Messenger
-
Sphingomyelins
-
fas Receptor
-
CASP3 protein, human
-
CASP8 protein, human
-
CASP9 protein, human
-
Caspase 3
-
Caspase 8
-
Caspase 9
-
Caspases
-
Sphingosine