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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Ashley, DM; Riffkin, CD; Muscat, AM; Knight, MJ; Kaye, AH; Novak, U; Hawkins, CJ

Published Date

  • October 1, 2005

Published In

Volume / Issue

  • 104 / 7

Start / End Page

  • 1487 - 1496

PubMed ID

  • 16080161

International Standard Serial Number (ISSN)

  • 0008-543X

Digital Object Identifier (DOI)

  • 10.1002/cncr.21323

Language

  • eng

Conference Location

  • United States