Distinct intracellular signaling in tumor necrosis factor-related apoptosis-inducing ligand- and CD95 ligand-mediated apoptosis.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in tumor cells but not in healthy cells. Similar to CD95 ligand (CD95L), TRAIL signaling requires ligand-receptor interaction; the downstream signaling molecules, such as Fas-associated death domain and caspase-8, also seem similar. Using cells stably expressing TRAIL and CD95L, we show that both TRAIL and CD95L induce apoptosis in the rat colon carcinoma cell line CC531. The mitochondrial damage (loss of mitochondrial membrane potential (MMP) and release of cytochrome c) observed after co-incubation with TRAIL-expressing cells occurs much earlier than that observed with CD95L-expressing cells. The decrease in MMP induced by both ligands was caspase-8-mediated; no difference in caspase-8 activation by TRAIL and CD95L was found. TRAIL, but not CD95L, induced activation of caspase-10. bcl-2 overexpression could not prevent TRAIL-induced mitochondrial dysfunction, whereas it completely prevented CD95L-mediated loss of MMP and cytochrome c release. The selective effect of TRAIL on tumor cells and the apparent inability of bcl-2 to block TRAIL-induced apoptosis suggest that TRAIL may offer a lead for cancer therapy in the future.
Velthuis
Jurjen H L
JH
Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, Wassenaarseweg 72, 2300 RA Leiden, The Netherlands. velthuis@lacdr.leidenuniv.nl
Rouschop
Kasper M A
KM
De Bont
Hans J G M
HJ
Mulder
Gerard J
GJ
Nagelkerke
J Fred
JF
D015703:Antigens, CD / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000502:physiology*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000494:pharmacology* / Q000502:physiology; D019014:fas Receptor / Q000502:physiology
D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D003574:Cytochrome c Group; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505655:Tnfsf10 protein, rat; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505528:Casp8 protein, rat; C506435:Casp9 protein, rat; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases