Bcl-X-L protects pancreatic adenocarcinoma cells against CD95-and TRAIL-receptor-mediated apoptosis

In this study we sought to clarify the role of the proapoptotic potential o f mitochondria in the death pathway emanating from the TRAIL (APO-2L) and C D95 receptors in pancreatic carcinoma cells. We focused on the role of the Bcl-2 family member Bcl-X-L, using three pancreatic carcinoma cell lines as a model system, two of which have high (Panc-1, PancTuI) and one has low ( Colo357) Bcl-X-L expression. In these cell lines, the expression of Bcl-X-L correlated with sensitivity to apoptosis induced by TRAIL or anti-CD95. Fl ow cytometric analysis revealed cell surface expression of TRAIL-Ri and TRA IL-R2 on PancTuI and Colo357, and TRAIL-R2 on Panc-1 cells. In Colo357 cell s retrovirally transduced with Bcl-X-L, caspase-8 activation in response to treatment with TRAIL or anti-CD95 antibody was not different from parental cells and EGFP-transfected controls, however, apoptosis was completely sup pressed as measured by the mitochondrial transmembrane potential Delta Psim , caspase-3 activity (PARP cleavage) and DNA-fragmentation, Inhibition of B cl-X-L function by overexpression of Bar or administration of antisense oli gonucleotides against Bcl-X-L mRNA resulted in sensitization of Panc-1 cell s to TRAIL and PancTuI cells to anti-CD95 antibody-induced cell death. The results show that Bcl-X-L can protect pancreatic cancer cells from CD95- an d TRAIL-mediated apoptosis, Thus, in these epithelial tumour cells the mito chondrially mediated 'type II' pathway of apoptosis induction is not only o perative regarding the CD95 system but also regarding the TRAIL system.