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 NFκB, 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 NFκB and JNK signalling in PancTuI cells. Caspase-mediated activation of NFκB 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 NFκB and ERK stimulating, caspase-dependent factor must operate downstream of the DISC in Colo357–BclxL cells.