Abstract
Radioresistance markedly impairs the efficacy of tumor radiotherapy and may involve antiapoptotic signal transduction pathways that prevent radiation-induced cell death. A common cellular response to genotoxic stress induced by radiation is the activation of the nuclear factor kappa B (NF-κB). NF-κB activation in turn can lead to an inhibition of radiation-induced apoptotic cell death. Thus, inhibition of NF-κB activation is commonly regarded as an important strategy to abolish radioresistance. Among other compounds, the fungal metabolite gliotoxin (GT) has been reported to be a highly selective inhibitor of NF-κB activation. Indeed, low doses of GT were sufficient to significantly enhance radiation-induced apoptosis in HL-60 cells. However, this effect turned out to be largely independent of NF-κB activation since radiation of HL-60 cells with clinically relevant doses of radiation induced only a marginal increase in NF-κB activity, and selective inhibition of NF-κB by SN50 did not result in a marked enhancement of GT-induced apoptosis. GT induced activation of JNKs, cytochrome c release from the mitochondria and potently stimulated the caspase cascade inducing cleavage of caspases −9, −8, −7 and −3. Furthermore, cleavage of the antiapoptotic protein X-linked IAP and downregulation of the G2/M-specific IAP-family member survivin were observed during GT-induced apoptosis. Finally, the radiation-induced G2/M arrest was markedly reduced in GT-treated cells most likely due to the rapid induction of apoptosis. Our data demonstrate that various other pathways apart from the NF-κB signaling complex can sensitize tumor cells to radiation and propose a novel mechanism for radiosensitization by GT, the interference with the G2/M checkpoint that is important for repair of radiation-induced DNA damage in p53-deficient tumor cells.
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Abbreviations
- AEBSF:
-
4-(2-aminoethyl)benzenesulfonyl fluoride
- CHAPS:
-
3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid
- CHX:
-
cycloheximide
- CLAC:
-
clasto-lactacystin
- COX:
-
cytochrome c oxidase
- Cyt c:
-
cytochrome c
- DTT:
-
dithiothreitol
- EMSA:
-
electrophoretic mobility shift assay
- FITL:
-
fluorescein isothiocyanate
- GT:
-
gliotoxin
- IκBα:
-
inhibitor of nuclear factor κα
- IR:
-
ionizing radiation
- JNK:
-
c-Jun NH2-terminal kinase
- MOPS:
-
morpholinepropanesulfonic acid
- NF-κB:
-
nuclear factor κB
- PAGE:
-
polyacrylamide gel electrophoresis
- PI:
-
propidium iodide
- z-VAD-fmk:
-
benzyloxy-carbonyl-Val-Ala-Asp-fluoromethylketone
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Acknowledgements
The skilful technical assistance of Stephanie Högner and Sabine Schirmer is gratefully acknowledged. The constructive advise of Dr Luitpold Distel and Dr Dieter Kaufmann-Bühler is greatly appreciated. The work was partially supported by the DFG-Grant Lo823/1-1.
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Baust, H., Schoke, A., Brey, A. et al. Evidence for radiosensitizing by gliotoxin in HL-60 cells: implications for a role of NF-κB independent mechanisms. Oncogene 22, 8786–8796 (2003). https://doi.org/10.1038/sj.onc.1206969
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DOI: https://doi.org/10.1038/sj.onc.1206969