Abstract: 【Objective】 To explore the mechanism of endoplasmic reticulum stress (ER stress) inducing glioblastoma stem cells (GSC) apoptosis via inhibiting PI3K/AKT/mTOR pathway. 【Methods】 Tumor samples were obtained from glioblastoma multiforme (GBM) patients after surgically resected specimens. Samples were washed

chopped

trypsinized

and filtered. The red cells were removed. The cells were cultured with tumour sphere medium (TSM) in vitro. GSC markers CD133

GFAP

Nestin and A2B5 were observed by immune-microscopy. After treating GSC (with/without transfecting with CHOP siRNA) by tunicamycin and thapsigargin

apoptosis induction was assessed by caspase 3/7 apoptosis assay; the percentage of cell viability was measured by MTS. The expression of caspase-3

C/EBP homologous protein (CHOP)

p-mTOR

p-AKT (Ser473) and p-AKT (Thr308) were examined by Western blot. 【Results】 The GSC spheres were formed in 7 days and the GSC markers CD133

GFAP

Nestin

and A2B5 were expressed. After activating ER stress

GSC cell death and apoptosis were induced significantly by up-regulatin caspase-3

CHOP and down-regulating p-mTOR

p-AKT (Ser473 and p-AKT (Thr308). However

transfecting with CHOP siRNA

the effects were attenuated. 【Conclusion】 ER stress might induce GSC apoptosis via inhibiting PI3K/AKT/mTOR pathway.