Sensitization of human glioblastomas to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by NF-kappaB inhibitors

Cancer Sci. 2004 Oct;95(10):840-4. doi: 10.1111/j.1349-7006.2004.tb02191.x.

Abstract

Glioblastoma is the most malignant form of primary brain tumor in adults, with no effective therapy and a low survival rate. TRAIL is a member of the TNF family, which selectively induces apoptosis in certain neoplastic cells, but not normal cells. In this study, we investigated the sensitivity of 7 human glioblastoma cell lines to TRAIL and the expression in them of TRAIL receptors. TRAIL exhibited significant cytotoxicity in 5 of 7 glioma cell lines. These glioblastoma cell lines expressed TRAIL-R2, but not TRAIL-R1, R3, or R4. However, no correlation was observed between the TRAIL sensitivity and the TRAIL-R2 expression level, suggesting that there is an additional determinant of TRAIL sensitivity. Treatments with NF-kappaB inhibitors, such as LLnL, MG132, and SN50, significantly increased the sensitivity of glioma cells to TRAIL. These results suggested that activation of NF-kappaB is a protective mechanism against TRAIL-induced cell death in some glioma cells, and thus NF-kappaB inhibitors may be useful to improve the clinical treatment of glioblastoma with TRAIL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology*
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Glioblastoma / metabolism
  • Glioblastoma / pathology*
  • Humans
  • Membrane Glycoproteins / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Recombinant Proteins / pharmacology
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Apoptosis Regulatory Proteins
  • Enzyme Inhibitors
  • Membrane Glycoproteins
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • Recombinant Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10A protein, human
  • TNFRSF10B protein, human
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • Protein-Serine-Threonine Kinases
  • NF-kappa B kinase