THE ANTICANCER DRUG ETOPOSIDE CAN INDUCE CASPASE-8 PROCESSING AND APOPTOSIS IN THE ABSENCE OF CD95 RECEPTOR-LIGAND INTERACTION

Caspase-8 (FLICE) can associate with and be activated by CD95 (APO-1/F as), an apoptosis-inducing member of the Tumour Necrosis Factor recept or family. We find that, in Jurkat T cells, the DNA damaging anti-canc er drug etoposide induces apoptosis and, surprisingly, processing of c aspase-8. Therefore, we have investigated whether etoposide involves C D95 receptor activation. We find that etoposide does not induce CD95 l igand expression at the mRNA level. In addition, blocking of CD95 rece ptor function with a specific antibody does not inhibit etoposide-indu ced apoptosis. Apparently, in Jurkat cells, etoposide can induce caspa se-8 processing and apoptosis in a CD95-independent fashion. Likewise, we find that thymocytes from the CD95-deficient lpr/lpr mouse strain readily undergo apoptosis in response to etoposide. Moreover, since in hibition of the secretory pathway with brefeldin A does not inhibit et oposide-induced apoptosis, we exclude the requirement for a newly synt hesized receptor ligand to induce the apoptotic pathway. We conclude t hat, at least in certain cell types, etoposide does not require CD95 r eceptor function to induce caspase-8 processing and apoptosis.