Paclitaxel-induced apoptosis in BJAB cells proceeds via a death receptor-independent, caspases-3/-8-driven mitochondrial amplification loop

Abstract

Caspase-8 is a key effector of death-receptor-triggered apoptosis. In a previous study, we demonstrated, however, that caspase-8 can also be activated in a death receptorindependent manner via the mitochondrial apoptosis pathway, downstream of caspase-3. Here, we show that caspases-3 and -8 mediate a mitochondrial amplification loop that is required for the optimal release of cytochrome c, mitochondrial permeability shift transition, and cell death during apoptosis induced by treatment with the microtubule-damaging agent paclitaxel (Taxol). In contrast, Smac release from mitochondria followed a different pattern, and therefore seems to be regulated independently from cytochrome c release. Taxol-induced cell death was inhibited by the use of synthetic, cellpermeable caspase-3-(zDEVD-fmk) or caspase-8-specific (zIETD-fmk) inhibitors. Apoptosis signaling was not affected by a dominant-negative FADD mutant (FADD-DN), thereby excluding a role of death receptor signaling in the amplification loop and drug-induced apoptosis. The inhibitor experiments were corroborated by the use of BJAB cells overexpressing the natural serpin protease inhibitor, cytokine response modifier A. These data demonstrate that the complete activation of mitochondria, release of cytochrome c, and execution of drug-induced apoptosis require a mitochondrial amplification loop that depends on caspases-3 and -8 activation. In addition, this is the first report to demonstrate death receptor-independent caspase-8 autoprocessing in vivo.

Celecoxib derivatives induce apoptosis via the disruption of mitochondrial membrane potential and activation of caspase 9

“…These data indicate that the celecoxib derivatives induced apoptosis via the mitochondrial pathway and that caspase 8 may act as a signal amplifier in the mitochondrial loop. 48,49 The involvement of the mitochondrial apoptotic pathway is further substantiated by our data showing that i) the celecoxib derivatives destabilize the mitochondrial membrane potential using the JC-1 indicator and ii) cyclosporin A, a mitochondrial membrane stabilizer, prevented celecoxib derivative induced mitochondrial membrane destabilization, caspase activation and apoptosis. The apoptotic response of the human oral cancer cell lines to the celecoxib derivatives is similar to the apoptotic responses of celecoxib in human lymphoma cell lines.…”

CD44 ligation induces apoptosis via caspase- and serine protease-dependent pathways in acute promyelocytic leukemia cells

“…However, we cannot exclude a possible involvement of the Fas-associated death domain protein, the main adaptor for transmitting the death receptor signal, or of an autoprocessing of caspase-8 as described in drug-induced apoptosis. 29,30 These various possibilities remain to be investigated in the context of A3D8-induced apoptosis of NB4 cells.…”

Endogenous Bak inhibitors Mcl-1 and Bcl-xL: differential impact on TRAIL resistance in Bax-deficient carcinoma

“…For analysis of cytochrome c release, cells were lysed in a hypotonic digitonin buffer as described previously (von Haefen et al, 2003).…”