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

Broaddus, V. Courtney; Dansen, Tobias B.; Abayasiriwardana, Keith S.; Wilson, Shannon M.; Finch, Andrew J.; Swigart, Lamorna Brown; Hunt, Abigail E.; Evan, Gérard I.

doi:10.1074/jbc.m408190200

Cited by 47 publications

(56 citation statements)

References 42 publications

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“…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.…”

Section: Discussionsupporting

confidence: 49%

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

et al. 2008

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Death receptors can directly (type I cells) or indirectly induce apoptosis by activating mitochondrial-regulated apoptosis (type II cells). The level of caspase 8 activation is thought to determine whether a cell is type I or II, with type II cells less efficient at activating this caspase following death receptor activation. FLICE-inhibitory protein (FLIP) blocks death receptor-mediated apoptosis by inhibiting caspase 8 activation; therefore, we assessed whether silencing FLIP could convert type II cells into type I. FLIP silencing-induced caspase 8 activation in Bax wild-type and null HCT116 colorectal cancer cells; however, complete caspase 3 processing and apoptosis were only observed in Bax wild-type cells. Bax-null cells were also more resistant to chemotherapy and tumor necrosis factor-related apoptosis inducing ligand and, unlike the Bax wild-type cells, were not sensitized to these agents by FLIP silencing. Further analyses indicated that release of second mitochondrial activator of caspases from mitochondria and subsequent inhibition of X-linked inhibitor of apoptosis protein (XIAP) was required to induce full caspase 3 processing and apoptosis following FLIP silencing. These results indicate that silencing FLIP does not necessarily bypass the requirement for mitochondrial involvement in type II cells. Furthermore, targeting FLIP and XIAP may represent a therapeutic strategy for the treatment of colorectal tumors with defects in mitochondrial-regulated apoptosis.

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Section: Discussionsupporting

confidence: 49%

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

et al. 2008

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“…Another possible mechanism was proposed by Broaddus et al (2005). Their data suggest that the synergistic effect between TRAIL and other DNA-damaging agents depends on BH-3 only protein, Bid.…”

Section: Discussionmentioning

confidence: 97%

Combined treatment of colorectal tumours with agonistic TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 and radiotherapy: enhanced effects in vitro and dose-dependent growth delay in vivo

et al. 2006

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We and others have demonstrated already that TRAIL (TNF-related apoptosis-inducing ligand) is a very promising candidate for molecular targeted anticancer therapy, especially when combined with ionizing radiation or other DNA-damaging agents. Agonist monoclonal antibodies that activate and are specific for the death signaling TRAIL receptors are an alternative method to stimulate the programmed cell death pathway. Phase 1 clinical trials have subsequently been conducted and shown a very good tolerability of these antibodies. In order to assess the efficacy of TRAIL receptor stimulation to induce cell death by this alternate method, we studied the combination of the agonistic-TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 with radiation in vitro and in vivo. Induction of apoptosis after combined treatment with TRAIL receptor antibodies HGS-ETR1 and/or HGS-ETR2 (0.01, 0.1, 1.0 mg/ml) and irradiation with 2, 5 or 10 Gy was determined by fluorescence microscopy and Western blot analysis of caspase-8 and PARP. The colorectal tumour cell lines Colo 205, HCT 116 and HCT-15 were used for in vitro experiments. Growth delay experiments were performed with combined treatment with fractionated irradiation (days 1-5 and 3 Gy single dose/day) and the receptor antibodies (intraperitonially, three different concentrations, application on days 1, 4 and 8) on Colo 205 xenograft-bearing NMRI (nu/nu) nude mice. HGS-ETR1 and HGS-ETR2 induced apoptotic cell death in a dose-dependent fashion and significantly increased cell death in combination with irradiation in vitro when compared to either irradiation or antibody treatment alone. The efficacy of the combined treatment seems to be at least partially Bax-dependent. Similar to the results from cell culture experiments, in vivo experiments demonstrated a dose-dependent delay in tumour growth after combined treatment. In vivo, in the Colo205 xenograft model, HGS-ETR2 revealed a higher activity than HGS-ETR1. This is the first study to demonstrate significant efficacy of combined treatment with the monoclonal agonistic TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 and ionising radiation in in vitro and in vivo models. We postulate that HGS-ETR1 and HGS-ETR2 will be very promising new agents in the field of molecular targeted multi-modality anticancer therapy.

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“…In other cell types, however, the mitochondrial pathway was essential for the combined effect. Specifically, in DU145 prostate carcinoma and HCT-116 colon carcinoma, the combined effect of IR and TRAIL relied on Bax (Ravi and Bedi, 2002;Wendt et al, 2005), in M28 mesothelioma it relied on Bid (Broaddus et al, 2005) and in a renal cell carcinoma it required Caspase-9 (Ramp et al, 2003). Jurkat cells are classically defined as type II cells that require a mitochondrial contribution to After 15 h incubation, cells were stimulated with FLAG-TRAIL precoupled to biotinylated anti-FLAG antibody for the indicated periods of time.…”

Section: Discussionmentioning

confidence: 99%

Ionizing radiation modulates the TRAIL death-inducing signaling complex, allowing bypass of the mitochondrial apoptosis pathway

et al. 2007

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In many tumor cell types, ionizing radiation (IR) or DNA-damaging anticancer drugs enhance sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, which is of great clinical interest. We have investigated the molecular mechanism underlying the response to combined modality treatment in p53-mutant Jurkat T leukemic cells overexpressing Bcl-2. These cells are largely resistant to individual treatment with TRAIL or IR, but sensitive to combined treatment, in vitro as well as in vivo. We demonstrate that IR and DNA-damaging anticancer drugs enable TRAIL receptor-2 and CD95/Fas to bypass the mitochondrial pathway for effector caspase activation. This was validated by RNA interference for Bax and Bak and by overexpression of dominant-negative Caspase-9. Improved effector caspase activation was neither caused by altered expression of proapoptotic components nor by impaired activity of inhibitor of apoptosis proteins or nuclear factor-jB signaling. Rather, we found that pretreatment of cells with IR caused quantitative and qualitative changes in death receptor signaling. It strongly improved the capacity of ligand-bound receptors to recruit FADD and activate Caspase-8 and -10 in the death-inducing signaling complex, while c-FLIP L levels were unaffected.

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

Cited by 47 publications

References 42 publications

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

Combined treatment of colorectal tumours with agonistic TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 and radiotherapy: enhanced effects in vitro and dose-dependent growth delay in vivo

Ionizing radiation modulates the TRAIL death-inducing signaling complex, allowing bypass of the mitochondrial apoptosis pathway

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