Resistance to CD95/Fas-induced and ceramide-mediated apoptosis of human melanoma cells is caused by a defective mitochondrial cytochrome c release

FEBS Lett. 2000 May 4;473(1):27-32. doi: 10.1016/s0014-5793(00)01491-5.

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