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Induction and intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apotosis in human malignant glioma cells.
Cancer Res. 2001 Feb 01; 61(3):1162-70.CR

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially triggers apoptosis in tumor cells versus normal cells, thus providing a therapeutic potential. In this study, we examined a large panel of human malignant glioma cell lines and primary cultures of normal human astrocytes for their sensitivity to TRAIL. Of 13 glioma cell lines, 3 were sensitive (80-100% death), 4 were partially resistant (30-79% death), and 6 were resistant (< 30% death). Normal astrocytes were also resistant. TRAIL-induced cell death was characterized by activation of caspase-8 and -3, poly(ADP-ribose) polymerase cleavage, and DNA fragmentation. Decoy receptor (DcR1 and DcR2) expression was limited in the glioma cell lines and did not correlate with TRAIL sensitivity. Both sensitive and resistant cell lines expressed TRAIL death receptor (DR5), adapter protein Fas-associated death domain (FADD), and caspase-8; but resistant cell lines expressed 2-fold higher levels of the apoptosis inhibitor phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes-15 kDa (PED/PEA-15). In contrast, cellular FADD-like IL-1beta-converting enzyme-like inhibitory protein (cFLIP) expression was similar in sensitive and resistant cells. Transfection of sense PED/PEA-15 cDNA in sensitive cells resulted in cell resistance, whereas transfection of antisense in resistant cells rendered them sensitive. Inhibition of protein kinase C (PKC) activity restored TRAIL sensitivity in resistant cells, suggesting that PED/ PEA-15 function might be dependent on PKC-mediated phosphorylation. In summary, TRAIL induces apoptosis in > 50% of glioma cell lines, and this killing occurs through activation of the DR pathway. This caspase-8-induced apoptotic cascade is regulated by intracellular PED/PEA-15, but not by cFLIP or decoy receptors. This pathway may be exploitable for glioma and possibly for other cancer therapies.

Authors+Show Affiliations

Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11221847

Citation

Hao, C, et al. "Induction and Intracellular Regulation of Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Mediated Apotosis in Human Malignant Glioma Cells." Cancer Research, vol. 61, no. 3, 2001, pp. 1162-70.
Hao C, Beguinot F, Condorelli G, et al. Induction and intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apotosis in human malignant glioma cells. Cancer Res. 2001;61(3):1162-70.
Hao, C., Beguinot, F., Condorelli, G., Trencia, A., Van Meir, E. G., Yong, V. W., Parney, I. F., Roa, W. H., & Petruk, K. C. (2001). Induction and intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apotosis in human malignant glioma cells. Cancer Research, 61(3), 1162-70.
Hao C, et al. Induction and Intracellular Regulation of Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Mediated Apotosis in Human Malignant Glioma Cells. Cancer Res. 2001 Feb 1;61(3):1162-70. PubMed PMID: 11221847.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Induction and intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apotosis in human malignant glioma cells. AU - Hao,C, AU - Beguinot,F, AU - Condorelli,G, AU - Trencia,A, AU - Van Meir,E G, AU - Yong,V W, AU - Parney,I F, AU - Roa,W H, AU - Petruk,K C, PY - 2001/2/28/pubmed PY - 2001/3/17/medline PY - 2001/2/28/entrez SP - 1162 EP - 70 JF - Cancer research JO - Cancer Res VL - 61 IS - 3 N2 - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially triggers apoptosis in tumor cells versus normal cells, thus providing a therapeutic potential. In this study, we examined a large panel of human malignant glioma cell lines and primary cultures of normal human astrocytes for their sensitivity to TRAIL. Of 13 glioma cell lines, 3 were sensitive (80-100% death), 4 were partially resistant (30-79% death), and 6 were resistant (< 30% death). Normal astrocytes were also resistant. TRAIL-induced cell death was characterized by activation of caspase-8 and -3, poly(ADP-ribose) polymerase cleavage, and DNA fragmentation. Decoy receptor (DcR1 and DcR2) expression was limited in the glioma cell lines and did not correlate with TRAIL sensitivity. Both sensitive and resistant cell lines expressed TRAIL death receptor (DR5), adapter protein Fas-associated death domain (FADD), and caspase-8; but resistant cell lines expressed 2-fold higher levels of the apoptosis inhibitor phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes-15 kDa (PED/PEA-15). In contrast, cellular FADD-like IL-1beta-converting enzyme-like inhibitory protein (cFLIP) expression was similar in sensitive and resistant cells. Transfection of sense PED/PEA-15 cDNA in sensitive cells resulted in cell resistance, whereas transfection of antisense in resistant cells rendered them sensitive. Inhibition of protein kinase C (PKC) activity restored TRAIL sensitivity in resistant cells, suggesting that PED/ PEA-15 function might be dependent on PKC-mediated phosphorylation. In summary, TRAIL induces apoptosis in > 50% of glioma cell lines, and this killing occurs through activation of the DR pathway. This caspase-8-induced apoptotic cascade is regulated by intracellular PED/PEA-15, but not by cFLIP or decoy receptors. This pathway may be exploitable for glioma and possibly for other cancer therapies. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/11221847/Induction_and_intracellular_regulation_of_tumor_necrosis_factor_related_apoptosis_inducing_ligand__TRAIL__mediated_apotosis_in_human_malignant_glioma_cells_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&amp;pmid=11221847 DB - PRIME DP - Unbound Medicine ER -