Over Expression of BCL2 and Low Expression of Caspase 8 Related to TRAIL Resistance in Brain Cancer Stem Cells

  • Qi, Ling (Department of Pathology, Jilin Medical College) ;
  • Ren, Kuang (Department of Pharmacology, Jilin Medical College) ;
  • Fang, Fang (Department of Immunology, Jilin Medical College) ;
  • Zhao, Dong-Hai (Department of Pathology, Jilin Medical College) ;
  • Yang, Ning-Jiang (Department of Pathology, Jilin Medical College) ;
  • Li, Yan (Department of Immunology, Jilin Medical College)
  • Published : 2015.07.13


Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been investigated as an effective agent to treat various cancers. Cancer stem cells are resistant to TRAIL treatment, but the mechanism of TRAIL resistance remains unknown. In this study, brain cancer stem cells were isolated by CD133 magnetic sorting, and the number of CD133 positive cells detected by flow cytometry. The self-renewing capacity of brain cancer stem cells was examined by a neurosphere formation assay, and the percentage of cell death after TRAIL treatment was examined by an MTS assay. Expression of DR5, FADD, caspase 8 and BCL2 proteins was detected by western blot. The amount of CD133 positive cells was enriched to 71% after CD133 magnetic sorting. Brain cancer stem cell neurosphere formation was significantly increased after TRAIL treatment. TRAIL treatment also reduced the amount of viable cells and this decrease was inhibited by a caspase 8 inhibitor or by the pan-caspase inhibitor z-VAD (P<0.05). Brain cancer stem cells expressed lower levels caspase 8 protein and higher levels of BCL2 protein when compared with CD133 negative cells (P<0.05). Our data suggest that TRAIL resistance is related to overexpression of BCL2 and low expression of caspase 8 which limit activation of caspase 8 in brain cancer stem cells.


Brain cancer stem cells;TRAIL;caspase 8;BCL2


Supported by : National Natural Science Foundation of China


  1. Zhao XD, He YY, Gao J, et al (2014). High expression of bcl-2 protein predicts favorable outcome in non-small cell lung cancer: evidence from a systematic review and meta-analysis. Asian Pac J Cancer Prev, 15, 8861-9.
  2. Zheng NG, Mo SJ, Li JP, et al (2014). Anti-CSC effects in human esophageal squamous cell carcinomas and eca109/9706 cells induced by nanoliposomal quercetin alone or combined with CD 133 antiserum. Asian Pac J Cancer Prev, 15, 8879-84.
  3. Capper D, Gaiser T, Hartmann C, et al (2009). Stem-cell-like glioma cells are resistant to TRAIL/Apo2L and exhibit down-regulation of caspase-8 by promoter methylation. Acta Neuropathol, 117, 445-56.
  4. Ding LJ, Yuan CJ, Wei F, et al (2011). Cisplatin restores TRAIL apoptotic pathway in glioblastoma-derived stem cells through up-regulation of DR5 and down-regulation of c-FLIP. Cancer Invest, 29, 511-520.
  5. Dirks PB (2010). Brain cancer stem cells: the cancer stem cell hypothesis writ large. Mol Oncol, 4, 420-30.
  6. Gao CM, Ding JH, Li SP, et al (2013). Polymorphisms in XRCC1 gene, alcohol drinking, and risk of colorectal cancer: a case-control study in Jiangsu Province of China. Asian Pac J Cancer Prev, 14, 6613-8.
  7. Li YC, Tzeng CC, Song JH, et al (2006). Genomic alterations in human malignant glioma cells associate with the cell resistance to the combination treatment with tumor necrosis factor-related apoptosis-inducing ligand and chemotherapy. Clin Cancer Res, 12, 2716-29.
  8. Bellail AC, Tse MC, Song JH, et al (2010). DR5-mediated DISC controls caspase-8 cleavage and initiation of apoptosis in human glioblastomas. J Cell Mol Med, 14, 1303-17.
  9. Bellail AC, Olson JJ, Yang X, et al (2012). A20 ubiquitin ligase-mediated polyubiquitination of RIP1 inhibits caspase-8 cleavage and TRAIL-induced apoptosis in glioblastoma. Cancer Discov, 2, 140-55.
  10. Li Z, Bao S, Wu Q, et al (2009). Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell, 15, 501-13.
  11. Qi L, Bellail AC, Rossi MR, et al (2011a). Heterogeneity of primary glioblastoma cells in the expression of caspase-8 and the response to TRAIL-induced apoptosis. Apoptosis, 16, 1150-64.
  12. Qi L, Jin H, Ding LJ, et al (2011b). CD133 magnetic sorting and biological characteristics of brain cancer stem cells. Jo Jilin University (Medicine Edition), 37, 441-4.
  13. Qi L, Yu HQ, Ding LJ, et al (2011c). Role of caspase-8 in glioblastoma resistance to TRAIL-induced apoptosis. J Jilin University (Medicine Edition), 37, 612-6.
  14. Qi L, Jin H, Zhao DH, et al (2014). Effect of schisandra lignans on the apoptosis of SHG-44 glioma neurospheres. Chin Pharm J, 49, 113-6.
  15. Qiu B, Wang Y, Tao J, et al (2012). Expression and correlation of Bcl-2 with pathological grades in human glioma stem cells. Oncol Rep, 28, 155-60.
  16. Singh SK, Hawkins C, Clarke ID, et al (2004). Identification of human brain tumour initiating cells. Nature, 432, 396-401.
  17. Wang R, Chadalavada K, Wilshire J, et al (2010). Glioblastoma stem-like cells give rise to tumour endothelium. Nature, 468, 829-33.
  18. Yuan X, Curtin J, Xiong Y, et al (2004). Isolation of cancer stemcells from adult glioblastoma multiforme. Oncogene, 23, 9392-400.

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