Caspase-8 activation independent of CD95/CD95-L interaction during paclitaxel-induced apoptosis in human colon cancer cells (HT29-D4).
Antimicrotubule agent-induced apoptosis was examined in the proliferating human colon cancer cell line HT29-D4. G2/M arrest and subsequent apoptosis were dose-dependent, both observed with 100 nM paclitaxel or docetaxel and 10 nM vinorelbine. Bcl-x(L) phosphorylation was observed simultaneously with mitotic block, then caspase-3 cleavage and poly(ADP-ribose) polymerase degradation were detected 48 hr later. By using both enzymatic assay and immunoblot detection of cleaved fragments, we showed that caspase-8, a central component of the CD95-induced apoptotic pathway, was significantly activated during paclitaxel exposure, contemporary to apoptosis occurrence. Caspase-8 activation and apoptosis were independent of CD95 ligation and evidenced only for concentrations inducing Bcl-x(L) phosphorylation and a decrease in mitochondria permeability. Similar results were obtained with docetaxel and vinca alkaloids. Thus, antimitotic drugs may induce apoptosis via caspase-8 activation independently of CD95/CD95-L. Caspase-8 may be a common mediator of anticancer drug-induced apoptosis that could represent a promising target for future therapies.
Gonçalves
A
A
UMR CNRS 6032, University of "la Méditerranée,", Marseille, France.
Braguer
D
D
Carles
G
G
André
N
N
Prevôt
C
C
Briand
C
C
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D003110:Colonic Neoplasms; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D019073:HT29 Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D008938:Mitosis / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051020:bcl-X Protein; D019014:fas Receptor / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; C494811:BCL2L1 protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D019014:fas Receptor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D017239:Paclitaxel