title: Role of caspases in CD95L- and TRAIL-induced non-apoptotic signalling in pancreatic tumour cells.
abstract: 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.
authors.affiliation: 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.
authors.forename: Daniela
authors.initials: D
authors.lastname: Siegmund
authors.forename: Stefanie
authors.initials: S
authors.lastname: Klose
authors.forename: Donghui
authors.initials: D
authors.lastname: Zhou
authors.forename: Bernd
authors.initials: B
authors.lastname: Baumann
authors.forename: Christian
authors.initials: C
authors.lastname: Röder
authors.forename: Holger
authors.initials: H
authors.lastname: Kalthoff
authors.forename: Harald
authors.initials: H
authors.lastname: Wajant
authors.forename: Anna
authors.initials: A
authors.lastname: Trauzold
mesh_terms: 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
chemical_list: 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