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CCNU-dependent potentiation of TRAIL/Apo2L-induced apoptosis in human glioma cells is p53-independent but may involve enhanced cytochrome c release.
Oncogene. 2001 Jul 12; 20(31):4128-37.O

Abstract

Death ligands such as CD95 ligand (CD95L) or tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L) induce apoptosis in radiochemotherapy-resistant human malignant glioma cell lines. The death-signaling TRAIL receptors 2 (TRAIL-R2/death receptor (DR) 5) and TRAIL-R1/DR4 were expressed more abundantly than the non-death-inducing (decoy) receptors TRAIL-R3/DcR1 and TRAIL-R4/DcR2 in 12 human glioma cell lines. Four of the 12 cell lines were TRAIL/Apo2L-sensitive in the absence of a protein synthesis inhibitor, cycloheximide (CHX). Three of the 12 cell lines were still TRAIL/Apo2L-resistant in the presence of CHX. TRAIL-R2 expression predicted sensitivity to apoptosis. Coexposure to TRAIL/Apo2L and cytotoxic drugs such as topotecan, lomustine (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, CCNU) or temozolomide resulted in synergistic killing. Synergistic killing was more often observed in cell lines retaining wild-type p53 activity (U87MG, LN-229) than in p53 mutant cell lines (LN-18, T98G, U373MG). Drug exposure resulted in enhanced TRAIL-R2 expression, but decreased TRAIL-R4 expression in U87MG cells. Ectopic expression of dominant-negative p53(V135A) abrogated the drug-induced changes in TRAIL-R2 and TRAIL-R4 expression, but had no effect on synergy. Thus, neither wild-type p53 function nor changes in TRAIL receptor expression were required for synergy. In contrast, synergy resulted possibly from drug-induced cytochrome c release from mitochondria, serving as an amplifier of the TRAIL/Apo2L-mediated cascade of caspase activation. These data provide novel insights into the role of the TRAIL/Apo2L system in malignant gliomas and illustrate that TRAIL/Apo2L-based immunochemotherapy may be an effective therapeutic strategy for these lethal neoplasms.

Authors+Show Affiliations

Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Tübingen, Medical School, Tübingen, Germany.No 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

Language

eng

PubMed ID

11464279

Citation

Röhn, T A., et al. "CCNU-dependent Potentiation of TRAIL/Apo2L-induced Apoptosis in Human Glioma Cells Is P53-independent but May Involve Enhanced Cytochrome C Release." Oncogene, vol. 20, no. 31, 2001, pp. 4128-37.
Röhn TA, Wagenknecht B, Roth W, et al. CCNU-dependent potentiation of TRAIL/Apo2L-induced apoptosis in human glioma cells is p53-independent but may involve enhanced cytochrome c release. Oncogene. 2001;20(31):4128-37.
Röhn, T. A., Wagenknecht, B., Roth, W., Naumann, U., Gulbins, E., Krammer, P. H., Walczak, H., & Weller, M. (2001). CCNU-dependent potentiation of TRAIL/Apo2L-induced apoptosis in human glioma cells is p53-independent but may involve enhanced cytochrome c release. Oncogene, 20(31), 4128-37.
Röhn TA, et al. CCNU-dependent Potentiation of TRAIL/Apo2L-induced Apoptosis in Human Glioma Cells Is P53-independent but May Involve Enhanced Cytochrome C Release. Oncogene. 2001 Jul 12;20(31):4128-37. PubMed PMID: 11464279.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CCNU-dependent potentiation of TRAIL/Apo2L-induced apoptosis in human glioma cells is p53-independent but may involve enhanced cytochrome c release. AU - Röhn,T A, AU - Wagenknecht,B, AU - Roth,W, AU - Naumann,U, AU - Gulbins,E, AU - Krammer,P H, AU - Walczak,H, AU - Weller,M, PY - 2001/01/19/received PY - 2001/02/22/revised PY - 2001/04/10/accepted PY - 2001/7/21/pubmed PY - 2001/8/3/medline PY - 2001/7/21/entrez SP - 4128 EP - 37 JF - Oncogene JO - Oncogene VL - 20 IS - 31 N2 - Death ligands such as CD95 ligand (CD95L) or tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L) induce apoptosis in radiochemotherapy-resistant human malignant glioma cell lines. The death-signaling TRAIL receptors 2 (TRAIL-R2/death receptor (DR) 5) and TRAIL-R1/DR4 were expressed more abundantly than the non-death-inducing (decoy) receptors TRAIL-R3/DcR1 and TRAIL-R4/DcR2 in 12 human glioma cell lines. Four of the 12 cell lines were TRAIL/Apo2L-sensitive in the absence of a protein synthesis inhibitor, cycloheximide (CHX). Three of the 12 cell lines were still TRAIL/Apo2L-resistant in the presence of CHX. TRAIL-R2 expression predicted sensitivity to apoptosis. Coexposure to TRAIL/Apo2L and cytotoxic drugs such as topotecan, lomustine (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, CCNU) or temozolomide resulted in synergistic killing. Synergistic killing was more often observed in cell lines retaining wild-type p53 activity (U87MG, LN-229) than in p53 mutant cell lines (LN-18, T98G, U373MG). Drug exposure resulted in enhanced TRAIL-R2 expression, but decreased TRAIL-R4 expression in U87MG cells. Ectopic expression of dominant-negative p53(V135A) abrogated the drug-induced changes in TRAIL-R2 and TRAIL-R4 expression, but had no effect on synergy. Thus, neither wild-type p53 function nor changes in TRAIL receptor expression were required for synergy. In contrast, synergy resulted possibly from drug-induced cytochrome c release from mitochondria, serving as an amplifier of the TRAIL/Apo2L-mediated cascade of caspase activation. These data provide novel insights into the role of the TRAIL/Apo2L system in malignant gliomas and illustrate that TRAIL/Apo2L-based immunochemotherapy may be an effective therapeutic strategy for these lethal neoplasms. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/11464279/CCNU_dependent_potentiation_of_TRAIL/Apo2L_induced_apoptosis_in_human_glioma_cells_is_p53_independent_but_may_involve_enhanced_cytochrome_c_release_ L2 - https://doi.org/10.1038/sj.onc.1204534 DB - PRIME DP - Unbound Medicine ER -