Activation of caspase-8 in drug-induced apoptosis of B-lymphoid cells is independent of CD95/Fas receptor-ligand interaction and occurs downstream of caspase-3

Abstract

The activation of caspase-8, a crucial upstream mediator of death receptor signaling, was investigated in epirubicinand Taxol IntroductionApoptosis, a morphologically and biochemically defined form of cell death, 1 plays a role in a wide variety of biologic systems, including tissue homeostasis and regulation of the immune system. 2,3 The process is a highly orchestrated cellular pathway leading to activation of the downstream death machinery. The central mediator and executioner of the death machinery is a proteolytic system involving a family of cysteinyl proteases, called caspases (for review, see Thornberry and Lazebnik 4 ). Triggering of the apoptotic cascade by different death stimuli, such as ionizing radiation 5 and chemotherapeutic drugs, 6 culminates in caspasedependent cleavage of a set of regulatory proteins, degradation of cellular DNA, and complete disassembly of the cell. Thus far, 14 caspase family members have been identified, and some of them, such as caspase-8, mediate apoptotic signals after the activation of death receptors. 7,8 Others, such as caspase-9, are part of the apoptosome and play a role in signal transduction after mitochondrial damage. 9 Recently, an endoplasmic-reticulum-specific pathway of apoptosis has been described that is mediated by caspase-12. 10 Previous data suggest that cytotoxic drugs induce cell death through CD95/Fas-CD95 ligand interaction, 11 and the relevance of this particular death pathway has been shown, for instance, in doxorubicin-induced apoptosis of leukemic T cells. 12 However, other groups were unable to confirm these findings and showed CD95/Fas-independent induction of apoptosis by chemotherapeutic drugs-for example, doxorubicin and etoposide-in Tlymphoma cells. 13,14 The finding that CD95/Fas-signaling and DNA damage induce different apoptosis-signaling pathways has also been shown in a murine and a human B-lymphoma cell line. 15 Furthermore, experimental evidence has been provided that neither FADD 16 nor caspase-8 17 is required for drug-induced apoptosis.In B cells, the induction of apoptosis plays important roles in humoral immunity. In this context, it has been shown that the antigen receptor BCR and the CD95/Fas receptor transduce pro-apoptotic signals in mature B cells (for review, see Tsubata 18 ). We previously showed that activation-induced apoptosis of normal and malignant B lymphocytes upon antigen-receptor ligation is independent of CD95/Fas and CD95/Fas ligand. 19 This has been confirmed by another study demonstrating that B-cell receptormediated apoptosis, in contrast to activation-induced T-cell apoptosis, is not mediated through known death receptor systems, nor does it involve the initial activation of caspase-8. 20 We nevertheless For personal use only. on May 12, 2018. by guest www.bloodjournal.org From observed that drug treatment leads to processing and activation of procaspase-8. We therefore focused our interest on the specific mechanisms leading to apoptotic death after the treatment of immature and mature B-lymphoma cells wi...

N-(4-hydroxyphenyl) retinamide (4HPR) enhances TRAIL-mediated apoptosis through enhancement of a mitochondrial-dependent amplification loop in ovarian cancer cell lines

“…Recent reports have shown that both caspase-8 and -9 can be activated downstream of each other in both drug-induced and death receptor-induced apoptosis. 45,[61][62][63][64] In apoptosis induced by death receptors, caspase-8 becomes active at the DISC. 44 The active caspase-8 can directly activate downstream caspases such as caspase-3 and -7.…”

RanBP1 downregulation sensitizes cancer cells to taxol in a caspase-3-dependent manner

“…The involvement of caspase-3 in the apoptotic response to RanBP1 downregulation is interesting in light of the notion that taxol, which suppresses MT dynamics and causes prometaphase arrest, also induces caspase-3 activation and eventually apoptosis (Ibrado et al, 1998;Oyaizu et al, 1999;Wieder et al, 2001;Lu et al, 2005;Impens et al, 2008). We therefore decided to investigate the combined effect of RanBP1 interference and taxol exposure.…”

The kiss of death: promises and failures of death receptors and ligands in cancer therapy

“…Activation of caspase-8 was blocked by preincubation of the B lymphoid cells with the caspase-3 specific inhibitor zDEVD-fmk. 93 Thus, in drug-induced apoptosis in B lymphoid cells the molecular order is represented by the hierarchical activation of mitochondria, caspase-3 and downstream caspase-8. In this system caspase-8 functions as an amplifying executioner rather than as an initiator caspase (Figure 2).…”

“…93,[149][150][151] This also holds true for the activation of caspase-8 during drug-induced apoptosis. 152 In contrast to the death-receptor/FADD-dependent pathway, caspase-8 activation is triggered in this situation by a receptor-independent, post-mitochondrial mechanism downstream of caspase-3 and functions as an amplifying executioner caspase during drug-induced apoptosis.…”