Evidence for radiosensitizing by gliotoxin in HL-60 cells: implications for a role of NF-kappa B independent mechanisms
2003 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 22, no 54, 8786-8796 p.Article in journal (Refereed) Published
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-kappaB). NF-kappaB activation in turn can lead to an inhibition of radiation-induced apoptotic cell death. Thus, inhibition of NF-kappaB 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-kappaB 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-kappaB activation since radiation of HL-60 cells with clinically relevant doses of radiation induced only a marginal increase in NF-kappaB activity, and selective inhibition of NF-kappaB 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-kappaB signaling complex can sensitize tumor cells to radiation and propose a novel mechanism for radio-sensitization by GT, the interference with the G2/M checkpoint that is important for repair of radiation-induced DNA damage in p53-deficient tumor cells.
Place, publisher, year, edition, pages
2003. Vol. 22, no 54, 8786-8796 p.
26s proteasome, c-jun, cytochrome-c, death, gliotoxin and radiosensitizing, induction, inhibition, ionizing-radiation, jnk, NF-kappa B, persistent activation, protein-kinase pathway, radiation-induced apoptosis, survivin, XIAP
Cancer and Oncology Biochemistry and Molecular Biology
IdentifiersURN: urn:nbn:se:liu:diva-87005DOI: 10.1038/sj.onc.1206969ISI: 000186844900016OAI: oai:DiVA.org:liu-87005DiVA: diva2:584213