Caspase 8 is absent or low in many ex vivo gliomas
journal contributionposted on 2005-10-01, 00:00 authored by David Ashley, C D Riffkin, Andrea Muscat, M J Knight, A H Kaye, U Novak, C J Hawkins
BACKGROUND: Better treatments are required urgently for patients with malignant glioma, which currently is incurable. Death ligands, such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), may offer promise for the treatment high-grade glioma if such ligands induce apoptotic signaling in vivo in glioma cells. Caspase 8 is required for death ligand signaling, and its levels may influence the sensitivity of glioma cells to death ligands. It also may act as a tumor suppressor protein. The authors analyzed caspase 8 expression levels in ex vivo glioma specimens and explored potential mechanisms of its regulation. METHODS: Eleven glioblastomas, 5 anaplastic astrocytomas, and 3 low-grade astrocytomas were studied. The levels of caspase 8, caspase 10, cellular FLICE inhibitory protein (c-FLIP), and signal transducer and activator of transcription (STAT)-1 were assayed using quantitative immunoblotting. Caspase 8 mRNA was measured by Northern blot analysis. The methylation status of the caspase 8 gene was determined by bisulfate modification of genomic DNA, cloning, and sequencing. Statistical analyses were performed using nonparametric (Spearman) correlations. RESULTS: Some ex vivo glioma samples lacked detectable caspase 8, with many expressing barely detectable levels. No tumors expressed significant amounts of caspase 10 or c-FLIP. A strong association was found between caspase 8 mRNA and protein levels. Neither expression of the transcription factor STAT-1 nor caspase 8 gene methylation correlated with caspase 8 levels. CONCLUSIONS: The absence of caspase 8 protein in many resected glioma samples implied that many patients with glioma may not benefit from death ligand-based treatments, unless caspase 8 (or caspase 10) protein expression can be elevated. Demethylating agents are unlikely to boost caspase 8 levels in glioma cells, but treatments that increase caspase 8 mRNA levels may up-regulate expression of the protein.
Pagination1487 - 1496
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Publication classificationC1.1 Refereed article in a scholarly journal
Copyright notice2005, American Cancer Society
caspase 8caspase 10STAT-1TRAILglioblastomaastrocytomaApo-2LBase SequenceBiomarkers, TumorBlotting, NorthernBrain NeoplasmsCaspasesDNA MethylationDNA, NeoplasmFemaleHumansMaleMolecular Sequence DataProbabilityReverse Transcriptase Polymerase Chain ReactionRisk AssessmentSampling StudiesSensitivity and SpecificityStatistics, NonparametricTissue Culture Techniques