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

TLR3 converts in cancer cells from an inflammatory to a death receptor and TLR3-induced cell death activates the extrinsic apoptosis pathway. Here, we demonstrate that activation of TLR3 triggers a form lysosomal cell death. Following the combinational treatment of IFN-1/poly(I:C) of the Caspase-8 deficient neuroblastoma cell line SH-SY5Y, lysosomes enlarge and accumulate before cells display characteristic apoptotic morphologies. However, caspases are not involved in signalling from TLR3 to the lysosome as 25 μM did not inhibit cell death. However, increasing zVAD concentrations to 50 μM which is known to inhibit cathepsins, as well as a specific cathepsin B inhibitor reduced TLR3-induced lysosomal cell death. Thus lysosomal cathepsins have a role in cell death execution and overtake the role of caspase-8 in inducing the apoptotic caspase cascade. Further in the caspase-8 positive neuroblastoma cell line SK-N-AS, knockdown of caspase-8 induces a switch from TLR3-induced apoptosis to lysosomal cell death. Taken together our data suggest that lysosomal cell death represents a default death mechanism, when caspase-8 is absent.