Synergistic effect of TRAIL and irradiation in elimination of glioblastoma stem-like cells

Clin Exp Med. 2018 Aug;18(3):399-411. doi: 10.1007/s10238-018-0504-7. Epub 2018 May 18.

Abstract

Glioblastoma multiforme (GBM) is the most common malignancy in central nervous system. A small subpopulation of GBM cells known as GBM stem-like cells (GSLCs) were supposed to be the most malignant cells among GBM cells as they are resistant to multiple therapies including radiotherapy. In this study, we set up two GSLCs cell lines from the two parental U87 and U251 glioma cell lines, and studied the expression of apoptosis-related genes alteration in GSLCs before and after irradiation. We found that one of the receptors of TNF-related apoptosis-inducing ligand (TRAIL), DR5, was dramatically up-regulated in GSLCs after irradiation (IR). Although GSLCs are resistant to both TRAIL and radiation treatment alone, the combined treatment with TRAIL and irradiation achieved maximum killing effect of GSLCs due to inducing the expression of DR5 and inhibiting the expression of cFLIP. Therefore, TRAIL and IR combined treatment would be a simple but practical therapeutic strategy for clinical application.

Keywords: DR5; Glioblastoma; Irradiation; Radioresistance; Stem-like cells; TRAIL.

MeSH terms

  • Apoptosis* / drug effects
  • Apoptosis* / radiation effects
  • CASP8 and FADD-Like Apoptosis Regulating Protein / antagonists & inhibitors
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics*
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • Central Nervous System Neoplasms / genetics
  • Central Nervous System Neoplasms / metabolism
  • Central Nervous System Neoplasms / pathology
  • Central Nervous System Neoplasms / therapy
  • Combined Modality Therapy
  • Founder Effect
  • Gamma Rays / therapeutic use*
  • Glioblastoma / genetics
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Glioblastoma / therapy
  • Humans
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Neoplastic Stem Cells / radiation effects
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / agonists
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / genetics
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*

Substances

  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10B protein, human
  • TNFSF10 protein, human