Abstract
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.
Highlights
Glioblastoma is the most common and aggressive brain tumor in humans, and until now no curative treatments were available (Qi et al, 2011a)
After Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatments, in expression in brain cancer stem cells (BCSC) when compared with CD133 we found that cell proliferation was significantly decreased negative cells (P>0.05, Figure 5 and 6)
Apoptosis is an important mechanism of death in of BCL2 was shown in BCSC (Figures 5 and 6), both cancer treatments
Summary
Glioblastoma is the most common and aggressive brain tumor in humans, and until now no curative treatments were available (Qi et al, 2011a). Recent studies suggest that cancer stem cells are tumor-initiating cells, and that these cells are responsible for resistance to radiation and chemotherapy (Wang et al, 2010; Dirks et al, 2011). Neurospheres are cancer stem cells isolated from glioblastomas using CD133 magnetic sorting (Singh et al, 2004). When cultured in serum-free medium containing growth factors these cells retain the genomic properties of the original glioblastomas (Li et al, 2006). CD133 was recently reported to be a cancer stem cell marker (Zheng et al, 2014). Further studies have shown that targeting hypoxia genes of stem-like cancer cells in glioblastoma inhibits cancer growth and progression (Li et al, 2009)
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