Sensitization of resistant lymphoma cells to irradiation-induced apoptosis by the death ligand TRAIL

Belka, Claus; Schmid, Benjamin; Marini, P.; Durand, E; Rudner, Justine; Faltin, Heidrun; Bamberg, M.; Schulze‐Osthoff, Klaus; Budach, Wilfried

doi:10.1038/sj.onc.1204318

Cited by 125 publications

(104 citation statements)

References 26 publications

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“…However, as compared to type II solid tumor cell lines, Jurkat cells may be less reliant on this pathway. At high doses of death ligand and prolonged incubation, the direct pathway suffices for apoptotic execution (Belka et al, 2001;Rudner et al, 2005). Possibly, therefore, improved inducer caspase activation by DNA-damaging stimuli is the common cause of the combined effects on apoptotic execution in all tumor cell types.…”

Section: Discussionmentioning

confidence: 99%

“…This has been shown both in vitro and upon xenografting of tumor cells in mice (Chinnaiyan et al, 2000;Belka et al, 2001). For certain cell lines, combined effects became more apparent when TRAIL was added 12-24 h after irradiation or chemotherapy (Singh et al, 2003;Marini et al, 2005), which indicates that DNA-damaging regimens condition cells to more effectively undergo TRAIL-induced apoptosis.…”

Section: Introductionmentioning

confidence: 89%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

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

et al. 2007

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“…This finding created great interest and suggested TRAIL or anti-DR5 antibodies, respectively, as potential anticancer drugs (Fulda and Debatin, 2004). Although TRAIL or DR5-antibodies showed only modest effects on experimental tumors, recent studies combining TRAIL with radiation or chemotherapeutic drugs, for example alkylphosphocholines or substances inducing DNAbreakage (Belka et al, 2001(Belka et al, , 2004Rohn et al, 2001;Jendrossek et al, 2002Jendrossek et al, , 2003El-Zawahry et al, 2005) revealed very effective induction of apoptosis and suggest that TRAIL or anti-DR5 antibodies might be used in combination with further chemotherapeutic drugs and/or irradiation.…”

Section: Introductionmentioning

confidence: 99%

TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis

2006

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We have previously shown that activation of the acid sphingomyelinase (ASM), the release of ceramide and the formation of ceramide-enriched membrane domains are central for the induction of apoptosis by CD95. Here, we demonstrate that tumor necrosis factor-related apoptosisinducing ligand (TRAIL) and CD95 activate the ASM via a redox mechanism resulting in release of ceramide and formation of ceramide-enriched membrane platforms. Ceramide-enriched membrane platforms serve to cluster DR5 upon stimulation. Antioxidants prevent TRAILmediated stimulation of ASM, the release of ceramide, the formation of ceramide-enriched membrane platforms and the induction of apoptosis by TRAIL. Further, ASMdeficient splenocytes fail to cluster DR5 in ceramideenriched membrane domains upon TRAIL stimulation and resist TRAIL-induced apoptosis, events that were restored by addition of natural C 16 -ceramide. A dose-response analysis indicates that ceramide-enriched membrane platforms greatly sensitized tumor cells to TRAIL-induced apoptosis. Our data indicate that ceramide-enriched membrane platforms are required for the signaling of TRAIL-DR5 complexes under physiological conditions.

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“…A number of studies have shown that cotreatment with chemotherapeutic agents and irradiation results in sensitisation of TRAIL-resistant tumour cell lines. [29][30][31][32][33] However, the mechanisms leading to TRAIL sensitivity are controversial. 5,[34][35][36][37][38][39][40][41] Upregulation of the apoptosis-inducing TRAIL receptors after treatment with 5-fluorouracil (5-FU) has been implicated in sensitising human leukaemic and glioma cells.…”

Section: Introductionmentioning

confidence: 99%

Enhanced caspase-8 recruitment to and activation at the DISC is critical for sensitisation of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by chemotherapeutic drugs

et al. 2004

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Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) exhibits potent antitumour activity upon systemic administration in mice without showing the deleterious side effects observed with other apoptosisinducing members of the TNF family such as TNF and CD95L. TRAIL may, thus, have great potential in the treatment of human cancer. However, about 60% of tumour cell lines are not sensitive to TRAIL. To evaluate the mechanisms of tumour resistance to TRAIL, we investigated hepatocellular carcinoma (HCC) cell lines that exhibit differential sensitivity to TRAIL. Pretreatment with chemotherapeutic drugs, for example, 5-fluorouracil (5-FU), rendered the TRAIL-resistant HCC cell lines sensitive to TRAIL-induced apoptosis. Analysis of the TRAIL death-inducing signalling complex (DISC) revealed upregulation of TRAIL-R2. Caspase-8 recruitment to and its activation at the DISC were substantially increased after 5-FU sensitisation, while FADD recruitment remained essentially unchanged. 5-FU pretreatment downregulated cellular FLICE-inhibitory protein (cFLIP) and specific cFLIP downregulation by small interfering RNA was sufficient to sensitise TRAIL-resistant HCC cell lines for TRAIL-induced apoptosis. Thus, a potential mechanism for TRAIL sensitisation by 5-FU is the increased effectiveness of caspase-8 recruitment to and activation at the DISC facilitated by the downregulation of cFLIP and the consequent shift in the ratio of caspase-8 to cFLIP at the DISC.

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Sensitization of resistant lymphoma cells to irradiation-induced apoptosis by the death ligand TRAIL

Cited by 125 publications

References 26 publications

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

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

TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis

Enhanced caspase-8 recruitment to and activation at the DISC is critical for sensitisation of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by chemotherapeutic drugs

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