Cell type specific involvement of death receptor and mitochondrial pathways in drug-induced apoptosis

Apoptosis in response to cellular stress such as treatment with cytotoxic d rugs is mediated by effector caspases (caspase-3) which can be activated by different initiator pathways, Here, we report on a cell type specific trig gering of death receptor and/or mitochondrial pathways upon drug treatment. In type I cells (BJAB), both the receptor and the mitochondrial pathway we re activated upon drug treatment, since blockade of either the receptor pat hway by overexpression of dominant negative FADD (FADD-DN) or of the mitoch ondrial pathway by overexpression of Bcl-X-L only partially inhibited apopt osis, Drug treatment induced formation of a FADD- and caspase-8-containing CD95 death-inducing signaling complex (DISC) in type I cells resulting in a ctivation of caspase-8 as the most apical caspase. Tn contrast, in type II cells (Jurkat), apoptosis was predominantly controlled by mitochondria, sin ce overexpression of Bcl-2 completely blocked drug-induced apoptosis, while overexpression of FADD-DN had no protective effect. In these cells, caspas es including caspase-8 were activated by mitochondria-driven signaling even ts and no DISC was detected despite expression levels of CD95, FADD and cas pase-8 proteins comparable to type I cells. Likewise, drug-induced CD95 agg regation was predominantly found in type I cells. Bid was cleaved prior to mitochondrial alterations in type I cells providing a molecular link betwee n caspase-8 activation and mitochondrial perturbations, whereas in type. TT cells, Bid was cleaved downstream of mitochondria, Our findings of a cell type specific response to cytotoxic drugs have implications for the identif ication of molecular parameters for chemosensitivity or resistance in diffe rent tumor cells.