Mechanisms involved in exogenous C2- and C6-ceramide-induced cancer cell toxicity.
Ceramides are important intracellular second messengers that play a role in the regulation of cell growth, differentiation, and programmed cell death. To determine whether ceramides can mediate the apoptosis of HCT116 and OVCAR-3 cancer cells, exogenous C2-, C6-, and C16-ceramides were used to mimic the endogenous lipid increase that follows a large variety of stresses. C2- and C6-ceramides (cell-permeable ceramide analogs), but not C16-ceramide, induced nuclear factor-kappaB (NF-kappaB) DNA-binding, caspase-3 activation, poly(ADP-ribose) polymerase degradation, and mitochondrial cytochrome c release, indicating that apoptosis occurs through the caspase cascade and the mitochondrial pathway. No difference in survival was observed between control cells and cells expressing mutated IkappaBalpha and treated with the permeable ceramides. This suggests that, at least in these cell lines, stable NF-kappaB inhibition did not modify the ceramide-induced cytotoxicity pathway. C6-ceramide also induced a double block in G1 and G2, thus emptying the S phase.
Fillet
Marianne
M
Laboratory of Clinical Chemistry and Human Genetics, CHU B35, University of Liège, Sart-Tilman, 4000, Liège, Belgium. marianne.fillet@ulg.ac.be
Bentires-Alj
Mohamed
M
Deregowski
Valerie
V
Greimers
Roland
R
Gielen
Jacques
J
Piette
Jacques
J
Bours
Vincent
V
Merville
Marie-Paule
MP
D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000494:pharmacology*; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D002518:Ceramides; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; C064769:N-acetylsphingosine; D016328:NF-kappa B; C101954:N-caproylsphingosine; C097760:N-palmitoylsphingosine; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D013110:Sphingosine