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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 volume 20, pages 4128–4137 (2001)Cite this article

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 p53V135A 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.

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Acknowledgements

The authors thank J Rieger (Tübingen, Germany) for help with the statistical analysis. This study was supported by grants from the Fortüne program of the University of Tübingen to M Weller and W Roth and by the BioFuture Grant of the BMBF to H Walczak. The authors thank A Ashkenazi (South San Francisco, CA, USA) for valuable discussions and for providing soluble TRAIL/Apo2L.

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Authors and Affiliations

  1. Department of Neurology, Laboratory of Molecular Neuro-Oncology, University of Tübingen, Medical School, Tübingen, Germany

    Till A Röhn, Bettina Wagenknecht, Wilfried Roth, Ulrike Naumann & Michael Weller

  2. Institute of Physiology, University of Tübingen, Medical School, Tübingen, Germany

    Erich Gulbins

  3. Department of Immunogenetics, German Cancer Research Center, Heidelberg, Germany

    Peter H Krammer

  4. Department of Apoptosis Regulation, German Cancer Research Center, Heidelberg, Germany

    Henning Walczak

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  1. Till A Röhn
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  2. Bettina Wagenknecht
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Correspondence to Michael Weller.

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Röhn, T., 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 20, 4128–4137 (2001). https://doi.org/10.1038/sj.onc.1204534

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