Analysis of FasL and TRAIL induced apoptosis pathways in glioma cells

FasL and TNF-related apoptosis-inducing ligand (TRAIL) belong to a subgroup of the TNF superfamily which induce apoptosis by binding to their death do main containing receptors. In the present study we have utilized a panel of seven cell lines derived from human malignant gliomas to characterize mole cular pathways through which FasL and TRAIL induce apoptosis in sensitive g lioma cells and the mechanisms of resistance in cell lines which survive th e death stimuli. Our findings indicate that FADD and Caspase-8 are essentia l for FasL and TRAIL mediated apoptosis in glioma cells. One sensitive cell line (D270) can be protected from FasL and TRAIL induced death by anti-apo ptotic Bcl-2 family members while another (D645) cannot, implying that thes e lines may represent glioma examples of type II and type I cells respectiv ely. For the first time we demonstrate resistance to FasL but not to TRAIL within the one glioma cell line. Furthermore, we report distinct mechanisms of resistance within different glioma lines, including downregulation of C aspase-8 in U373MG. Cycloheximide sensitized four of the resistant cell lin es suggesting the presence of labile inhibitors. None of the known apoptosi s inhibitors examined accounted for the observed resistance, suggesting nov el inhibitors may exist in glioma cells.