Open AccessTRAIL Triggers Apoptosis in Human Malignant Glioma Cells Through Extrinsic and Intrinsic Pathways
Author(s) -
Song Jin H.,
Song Doyoun K.,
Pyrzynska Beata,
Petruk Kenneth C.,
Meir Erwin G.,
Hao Chunhai
Publication year - 2003
Publication title -
brain pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.986
H-Index - 132
eISSN - 1750-3639
pISSN - 1015-6305
DOI - 10.1111/j.1750-3639.2003.tb00484.x
Subject(s) - apoptosis , glioma , cancer research , camptothecin , caspase , tumor necrosis factor alpha , programmed cell death , cisplatin , etoposide , cell culture , biology , intrinsic apoptosis , chemistry , microbiology and biotechnology , immunology , chemotherapy , biochemistry , genetics
Many malignant glioma cells express death receptors for tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL), yet some of these cells are resistant to TRAIL. Here, we examined signaling events in TRAIL‐induced apoptosis and searched for therapeutic agents that could overcome TRAIL resistance in glioma cells. TRAIL induced apoptosis through death receptor 5 (DR5) and was mediated by caspase‐8‐initiated extrinsic and intrinsic mitochondrial pathways in sensitive glioma cell lines. TRAIL also triggered apoptosis in resistant glioma cell lines through the same pathways, but only if the cells were pretreated with chemotherapeutic agents, cisplatin, camptothecin and etoposide. Previous studies suggested that this was due to an increase in DR5 expression in wild‐type TP53 cells, but this mechanism did not account for cells with mutant TP53. Here, we show that a more general effect of these agents is to down regulate caspase‐8 inhibitor c‐FLIP S (the short form of cellular Fasassociated death domain‐like interleukin‐1‐converting enzyme‐inhibitory protein) and up‐regulate Bak, a pro‐apoptotic Bcl‐2 family member, independently of cell's TP53 status. Furthermore, we showed that TRAIL alone or in combination with chemotherapeutic agents, induced apoptosis in primary tumor cultures from patients with malignant gliomas, reinforcing the potential of TRAIL as an effective therapeutic agent for malignant gliomas.