Role of caspases in CD95L- and TRAIL-induced non-apoptotic signalling in pancreatic tumour cells.
The CD95 and TRAIL death receptors can potently stimulate proinflammatory signalling, especially in apoptosis resistant cells. Here, we show that caspases are of cell type-specific relevance for non-apoptotic death receptor signalling in pancreatic tumour cells. Inhibition of caspases by zVAD-fmk strongly enhanced the proinflammatory response in PancTuI, BxPc3 and Panc89 cells, but inhibited this response in Colo357 cells as well as in apoptosis-resistant Colo357-BclxL cells overexpressing BclxL. To characterize the role of caspases in non-apoptotic death receptor signalling, we analysed CD95L- and TRAIL-induced signalling pathways in Colo357-BclxL cells in comparison with PancTuI cells. Both death ligands induced NFkappaB, ERKs, JNK and p38 in Colo357-BclxL cells and except for ERKs also in PancTuI cells. However, inhibition of caspases with zVAD-fmk resulted in strong inhibition of all these signalling pathways in Colo357-BclxL, but enhanced NFkappaB and JNK signalling in PancTuI cells. Caspase-mediated activation of NFkappaB and ERKs were involved in CD95L- and TRAIL-induced up-regulation of proinflammatory genes in Colo357-BclxL cells. At the level of the DISC we did not observe any significant differences in recruitment or processing of FADD, caspase-8, FLIP, TRAF2 and RIP between PancTuI and Colo357-BclxL cells. Consequently, an NFkappaB and ERK stimulating, caspase-dependent factor must operate downstream of the DISC in Colo357-BclxL cells.
Siegmund
Daniela
D
Department of Molecular Internal Medicine, Medical Clinic and Polyclinic II, University of Wuerzburg, and Division of Molecular Oncology, Clinic for General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.
Klose
Stefanie
S
Zhou
Donghui
D
Baumann
Bernd
B
Röder
Christian
C
Kalthoff
Holger
H
Wajant
Harald
H
Trauzold
Anna
A
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D053222:Fas Ligand Protein / Q000494:pharmacology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D051020:bcl-X Protein / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053222:Fas Ligand Protein; D018836:Inflammation Mediators; D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D053221:TNF-Related Apoptosis-Inducing Ligand; D051020:bcl-X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D048049:Extracellular Signal-Regulated MAP Kinases; D053181:Caspase 8; D020169:Caspases