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

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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.

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Acknowledgments

We thank Diane Lawson for her technical support. This work was supported by National Institutes of Health grant CA129687 (C.H.) and Southeastern Brain Tumor Foundation research award (C.H.). C.H. was a Georgia Cancer Coalition Distinguished Scholar.

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Authors and Affiliations

  1. Department of Pathology & Laboratory Medicine, Radiation Oncology, and Neurosurgery, Winship Cancer Institute, Emory University School Medicine, 1365-C Clifton Road, Atlanta, GA, 30322, USA

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

  2. Department of Pediatrics, University of Oklahoma Health Sciences Center, 941 Stanton L. Young Blvd., BSEB 224, Oklahoma City, OK, 73104, USA

    Hui Pang & Shibo Li

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  1. Ling Qi
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  2. Anita C. Bellail
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Correspondence to Chunhai Hao.

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Ling Qi and Anita C. Bellail contributed equally to this study.

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Qi, L., Bellail, A.C., Rossi, M.R. et al. Heterogeneity of primary glioblastoma cells in the expression of caspase-8 and the response to TRAIL-induced apoptosis. Apoptosis 16, 1150–1164 (2011). https://doi.org/10.1007/s10495-011-0645-6

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  • DOI: https://doi.org/10.1007/s10495-011-0645-6

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