Bid Mediates Apoptotic Synergy between Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) and DNA Damage

Lung Biology Center, San Francisco General Hospital, University of California San Francisco, San Francisco, California 94143-0854, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2005; 280(13):12486-93. DOI: 10.1074/jbc.M408190200
Source: PubMed


The death ligand, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), has shown great promise for inducing apoptosis selectively in tumors. Although many tumor cells are resistant to TRAIL-induced apoptosis alone, they can often be sensitized by co-treatment with DNA-damaging agents such as etoposide. However, the molecular mechanism underlying this therapeutically important synergy is unknown. We explored the mechanism mediating TRAIL-DNA damage apoptotic synergy in human mesothelioma cells, a tumor type particularly refractory to existing therapies. We show that Bid, a cytoplasmic Bcl-2 homology domain 3-containing protein activated by caspase 8 in response to TRAIL ligation, is essential for TRAIL-etoposide apo-ptotic synergy and, furthermore, that exposure to DNA damage primes cells to induction of apoptosis by otherwise sublethal levels of activated Bid. Finally, we show that the extensive caspase 8 cleavage seen during TRAIL-etoposide synergy is a consequence and not a cause of the apoptotic cascade activated downstream of Bid. These data indicate that TRAIL-etoposide apoptotic synergy arises because DNA damage increases the inherent sensitivity of cells to levels of TRAIL-activated Bid that would otherwise be insufficient for apoptosis. Such studies indicate how the adroit combination of differing proapoptotic and sublethal signals can provide an effective strategy for treating refractory tumors.

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    • "With the exception of cancers in which essential components of the extrinsic cell death pathway are mutated or silenced (resulting, for example, in inactivation of TRAIL receptors or caspase-8), co-drugging has been shown to increase the efficacy of TRAIL in cell lines, tumor models and patients (Ashkenazi and Herbst 2008). Sub-lethal doses of chemotherapy or ionizing radiation are known to sensitize resistant cancer cells to TRAIL-induced apoptosis via modulation of TRAIL receptors, DISC or mitochondrial components (Broaddus et al 2005, Di Pietro et al 2001, Ehrhardt et al 2008, Galligan et al 2005, Ganten et al 2004, Keane et al 1999, Morizot et al 2010). Drugs that inhibit histone deacetylases or the proteasome (which modulate gene expression and protein stability, respectively) have also been shown to be effective in overcoming resistance to TRAIL in cell lines and tumor models (Bagci-Onder et al 2012, Brooks et al 2005, Butler et al 2006, Frew et al 2008, Inoue et al 2004, Kabore et al 2006, Vanoosten et al 2005). "
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    ABSTRACT: TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) holds promise as an anti-cancer therapeutic but efficiently induces apoptosis in only a subset of tumor cell lines. Moreover, even in clonal populations of responsive lines, only a fraction of cells dies in response to TRAIL and individual cells exhibit cell-to-cell variability in the timing of cell death. Fractional killing in these cell populations appears to arise not from genetic differences among cells but rather from differences in gene expression states, fluctuations in protein levels and the extent to which TRAIL-induced death or survival pathways become activated. In this study, we ask how cell-to-cell variability manifests in cell types with different sensitivities to TRAIL, as well as how it changes when cells are exposed to combinations of drugs. We show that individual cells that survive treatment with TRAIL can regenerate the sensitivity and death-time distribution of the parental population, demonstrating that fractional killing is a stable property of cell populations. We also show that cell-to-cell variability in the timing and probability of apoptosis in response to treatment can be tuned using combinations of drugs that together increase apoptotic sensitivity compared to treatment with one drug alone. In the case of TRAIL, modulation of cell-to-cell variability by co-drugging appears to involve a reduction in the threshold for mitochondrial outer membrane permeabilization.
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    • "This sub-network suggests that HCV may be able to repress the expressions of several key genes in a number of HCV pathways via miR-16, miR-215, or both. For example, miR-16 targets MAPK14 (p38 MAPK) and BID (also a miR-215 target), which are two key regulators in apoptosis-associated pathways [52,53]. The induction of apoptosis among virus-infected cells is an effective host mechanism against virus infection. "
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    • "The BH3 family member Bid mediates the cross-talk between the extrinsic and intrinsic apoptotic pathways (Li et al., 1998). Earlier studies have shown that the overexpression of a dominant negative Bid construct inhibited apoptosis induced by both the Fas and TRAIL receptors in Jurkat cells (Werner et al., 2002), and Bid has been reported to regulate the synergy between TRAIL and epotoside in M28 and REN cells (Broaddus et al., 2005). We found that Bid is critical for FLIP silencing-induced processing of caspase 3 and cell death in the HCT116 and HT29 cells, indicating that mitochondrial activation is required for cell death to occur. "
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