Caspase 8 is absent or low in many ex vivo gliomas.

Abstract

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.

• Authors: David M Ashley, Christopher D Riffkin, Andrea M Muscat, Melissa J Knight, Andrew H Kaye, Ulrike Novak, Christine J Hawkins
• Journal: Cancer (Cancer) Vol. 104 Issue 7 Pg. 1487-96 (Oct 01 2005) ISSN: 0008-543X [Print] United States
• PMID: 16080161 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• DNA, Neoplasm
• CASP8 protein, human
• Caspase 10
• Caspase 8
• Caspases
• CASP10 protein, human

Topics

• Astrocytoma (metabolism, pathology)
• Base Sequence
• Biomarkers, Tumor (analysis, metabolism)
• Blotting, Northern
• Brain Neoplasms (metabolism, pathology)
• Caspase 10
• Caspase 8
• Caspases (analysis, metabolism)
• DNA Methylation
• DNA, Neoplasm (analysis)
• Female
• Glioblastoma (metabolism, pathology)
• Humans
• Male
• Molecular Sequence Data
• Probability
• Reverse Transcriptase Polymerase Chain Reaction (methods)
• Risk Assessment
• Sampling Studies
• Sensitivity and Specificity
• Statistics, Nonparametric
• Tissue Culture Techniques