Heterogeneity of primary glioblastoma cells in the expression of caspase-8 and the response to TRAIL-induced apoptosis

Ling Qi, Anita C. Bellail, Michael R. Rossi, Zhaobin Zhang, Hui Pang, Stephen Hunter, Cynthia Cohen, Carlos S. Moreno, Jeffrey J. Olson, Shibo Li, Chunhai Hao

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Recent studies suggest that cancer stem cells (CSCs) are responsible for cancer resistance to therapies. We therefore investigated how glioblastoma-derived CSCs respond to the treatment of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Neurospheres were generated from glioblastomas, characterized for CSC properties including self-renewal, cell differentiation and xenograft formation capacity, and analyzed for TRAIL-induced apoptosis, CASP8 genomic status, and caspase-8 protein expression. The neurosphere NSC326 was sensitive to TRAIL-induced apoptosis as evidenced by cell death and caspase-8, -3, and -7 enzymatic activities. In contrast, however, the neurosphere NSC189 was TRAIL-resistant. G-banding analysis identified five chromosomally distinguishable cell populations in the neurospheres. Fluorescence in situ hybridization revealed the variation of chromosome 2 copy number in these populations and the loss of CASP8 locus in 2q33-34 region in a small set of cell populations in the neurosphere. Immunohistochemistry of NSC189 cell blocks revealed the lack of caspase-8 protein in a subset of neurosphere cells. Western blotting and immunohistochemistry of human glioblastoma tumors demonstrated the expression of caspase-8 protein in the vast majority of the tumors as compared to normal human brain tissues that lack the caspase-8 expression. This study shows heterogeneity of glioblastomas and derived CSCs in the genomic status of CASP8, expression of caspase-8, and thus responsiveness to TRAIL-induced apoptosis. Clinic trials may consider genomic analysis of the cancer tissue to identify the genomic loss of CASP8 and use it as a genomic marker to predict the resistance of glioblastomas to TRAIL apoptosis pathway-targeted therapies.

Original languageEnglish (US)
Pages (from-to)1150-1164
Number of pages15
JournalApoptosis
Volume16
Issue number11
DOIs
StatePublished - Nov 1 2011
Externally publishedYes

Keywords

  • Apoptosis
  • Cancer stem cells
  • Caspase-8
  • Glioblastoma
  • TRAIL

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Cancer Research

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  • Cite this

    Qi, L., Bellail, A. C., Rossi, M. R., Zhang, Z., Pang, H., Hunter, S., Cohen, C., Moreno, C. S., Olson, J. J., Li, S., & Hao, C. (2011). Heterogeneity of primary glioblastoma cells in the expression of caspase-8 and the response to TRAIL-induced apoptosis. Apoptosis, 16(11), 1150-1164. https://doi.org/10.1007/s10495-011-0645-6