Caspase-8 deficiency induces a switch from TLR3 induced apoptosis to lysosomal cell death in neuroblastoma

In Cancer cells only, TLR3 acquires death receptor properties by efficiently triggering the extrinsic pathway of Apoptosis with Caspase-8 as apical protease. Here, we demonstrate that in the absence of Caspase-8, activation of TLR3 can trigger a form of programmed cell death, which is distinct from classical Apoptosis. When TLR3 was activated in the Caspase-8 negative neuroblastoma cell line SH-SY5Y, cell death was accompanied by lysosomal permeabilization. Despite caspases being activated, lysosomal permeabilization as well as cell death were not affected by blocking caspase-activity, positioning lysosomal membrane permeabilization (LMP) upstream of Caspase activation. Taken together, our data suggest that LMP with its deadly consequences represents a "default" death mechanism in Cancer cells, when Caspase-8 is absent and Apoptosis cannot be induced.