TRAIL Triggers Apoptosis in Human Malignant Glioma Cells Through Extrinsic and Intrinsic Pathways

Jin H. Song, Doyoun K. Song, Beata Pyrzynska, Kenneth C. Petruk, Erwin G. Van Meir, Chunhai Hao

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

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 downregulate caspase-8 inhibitor c-FLIPs (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.

Original languageEnglish (US)
Pages (from-to)539-553
Number of pages15
JournalBrain Pathology
Volume13
Issue number4
StatePublished - Oct 1 2003
Externally publishedYes

Fingerprint

Glioma
Apoptosis
TNF-Related Apoptosis-Inducing Ligand Receptors
Caspase 8
Cell Line
Caspase 1
Camptothecin
Death Domain Receptors
Caspase Inhibitors
Etoposide
Cisplatin
Cell Death
Up-Regulation
Down-Regulation
Tumor Necrosis Factor-alpha
Ligands
Therapeutics
Neoplasms
Proteins

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neuroscience(all)
  • Clinical Neurology

Cite this

Song, J. H., Song, D. K., Pyrzynska, B., Petruk, K. C., Van Meir, E. G., & Hao, C. (2003). TRAIL Triggers Apoptosis in Human Malignant Glioma Cells Through Extrinsic and Intrinsic Pathways. Brain Pathology, 13(4), 539-553.

TRAIL Triggers Apoptosis in Human Malignant Glioma Cells Through Extrinsic and Intrinsic Pathways. / Song, Jin H.; Song, Doyoun K.; Pyrzynska, Beata; Petruk, Kenneth C.; Van Meir, Erwin G.; Hao, Chunhai.

In: Brain Pathology, Vol. 13, No. 4, 01.10.2003, p. 539-553.

Research output: Contribution to journalArticle

Song, JH, Song, DK, Pyrzynska, B, Petruk, KC, Van Meir, EG & Hao, C 2003, 'TRAIL Triggers Apoptosis in Human Malignant Glioma Cells Through Extrinsic and Intrinsic Pathways', Brain Pathology, vol. 13, no. 4, pp. 539-553.
Song JH, Song DK, Pyrzynska B, Petruk KC, Van Meir EG, Hao C. TRAIL Triggers Apoptosis in Human Malignant Glioma Cells Through Extrinsic and Intrinsic Pathways. Brain Pathology. 2003 Oct 1;13(4):539-553.
Song, Jin H. ; Song, Doyoun K. ; Pyrzynska, Beata ; Petruk, Kenneth C. ; Van Meir, Erwin G. ; Hao, Chunhai. / TRAIL Triggers Apoptosis in Human Malignant Glioma Cells Through Extrinsic and Intrinsic Pathways. In: Brain Pathology. 2003 ; Vol. 13, No. 4. pp. 539-553.
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