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Adenoviral expression of XIAP antisense RNA induces apoptosis in glioma cells and suppresses the growth of xenografts in nude mice

Gene Therapy volume 14, pages 147–161 (2007)Cite this article

A Corrigendum to this article was published on 18 September 2007

Abstract

The expression of inhibitor of apoptosis (IAP) family members contributes to the resistance of human cancers to apoptosis induced by radiotherapy and chemotherapy. We report that the infection of malignant glioma cells and several other tumor cell lines with adenoviruses encoding antisense RNA to X-linked IAP (XIAP) depletes endogenous XIAP levels and promotes global caspase activation and apoptosis. In contrast, non-neoplastic SV-FHAS human astrocytes and other non-neoplastic cells express XIAP at very low levels and resist these effects of adenovirus-expressing XIAP antisense RNA (Ad-XIAP-as). Caspase inhibitors such as z-Val-Ala-DL-Asp(OMe)-fluoromethylketone (zVAD-fmk) delay caspase processing and XIAP depletion, suggesting that XIAP depletion results both from antisense-mediated interference with protein synthesis and proteolytic cleavage by activated caspases. However, zVAD-fmk neither prevents nor delays cell death, indicating a caspase-independent pathway to cell death triggered by IAP depletion. Similarly, B-cell lymphoma-XL (BCL-XL) inhibits caspase activity, but fails to rescue from apoptosis. Loss of p65/nuclear factor-κB (NF-κB) protein and NF-κB activity is an early event triggered by Ad-XIAP-as and probably involved in Ad-XIAP-as-induced apoptosis. Finally, Ad-XIAP-as gene therapy induces cell death in intracranial glioma xenografts, prolongs survival in nude mice and may reduce tumorigenicity in synergy with Apo2L/TNF-related apoptosis-inducing ligand (TRAIL) in vivo. Altogether, these data define a powerful survival function for XIAP and reinforce its possible role as a therapeutic target in human glioma cells.

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Acknowledgements

This study was supported by a grant from the Deutsche Krebshilfe to MW and UN.

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Authors and Affiliations

  1. Department of General Neurology, Laboratory of Molecular Neuro-Oncology, Hertie Institute for Clinical Brain Research, Tübingen, Germany

    U Naumann, O Bähr, S Altenberend, W Wick & M Weller

  2. Institute of Pathology, School of Medicine, University of Tübingen, Tübingen, Germany

    H Wolburg

  3. Department of Pediatrics, Molecular Genetics Research, Solange Gauthier Karsh Laboratory, University of Ottawa, Ottawa, Canada

    P Liston

  4. Genentech, South San Francisco, CA, USA

    A Ashkenazi

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Correspondence to U Naumann.

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Naumann, U., Bähr, O., Wolburg, H. et al. Adenoviral expression of XIAP antisense RNA induces apoptosis in glioma cells and suppresses the growth of xenografts in nude mice. Gene Ther 14, 147–161 (2007). https://doi.org/10.1038/sj.gt.3302845

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