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Mechanisms of resistance of human glioma cells to Apo2 ligand/TNF-related apoptosis-inducing ligand.

AbstractBACKGROUND:
Many tumor cells are resistant to Apo2L/TRAIL-induced apoptosis in the absence of inhibitors of protein synthesis. Apo2L/TRAIL, in addition to induction of apoptosis, may therefore also activate survival pathways.
METHODS:
Here we investigated whether such survival pathways mediate resistance to Apo2L.0-induced apoptosis in human glioma cells.
RESULTS:
Apo2L.0 induced the phosphorylation of ERK1/2, but not of Akt. This effect was unaffected by caspase inhibition. Inhibitors of protein synthesis, PI3 kinase, ERK kinase, NF-kappaB or casein kinase 2 sensitized for Apo2L.0-induced apoptosis to a different extent in a panel of human malignant glioma cell lines. However, none of the sensitizers overcame resistance mediated by ectopic expression of the viral caspase 8 inhibitor, crm-A. Primary glioma cultures were almost completely resistant to Apo2L.0-induced cell death even in the presence of the inhibitors. Caspase-8 was expressed in these cells whereas only weak expression of DR5 was detected. Transient expression of DR5 conferred sensitivity to Apo2L.0.
CONCLUSION:
These data challenge the view that specific cell lines harbour specific mechanisms of resistance to Apo2L/TRAIL. Weak expression of DR5 in primary glioma might limit the therapeutic application of Apo2L/TRAIL in human glioblastoma patients.
AuthorsJohannes Rieger, Brigitte Frank, Michael Weller, Wolfgang Wick
JournalCellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 20 Issue 1-4 Pg. 23-34 ( 2007) ISSN: 1015-8987 [Print] Germany
PMID17595512 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Recombinant Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • Extracellular Signal-Regulated MAP Kinases
  • CASP8 protein, human
  • Caspase 8
Topics
  • Apoptosis (drug effects)
  • Caspase 8 (metabolism)
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • Drug Resistance, Neoplasm
  • Extracellular Signal-Regulated MAP Kinases (metabolism)
  • Glioma (drug therapy, genetics, metabolism, pathology)
  • Humans
  • Phosphorylation
  • Receptors, TNF-Related Apoptosis-Inducing Ligand (genetics, metabolism)
  • Recombinant Proteins (genetics, metabolism, pharmacology)
  • Signal Transduction (drug effects)
  • TNF-Related Apoptosis-Inducing Ligand (pharmacology)
  • Transfection

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