Abstract
Survival of patients with Glioblastoma Multiforme (GM), a highly malignant brain tumor, remains poor despite concerted efforts to improve therapy. The median survival of patients with GM has remained approximately 1 year regardless of the therapeutic approach. Since radiation therapy is the most effective adjuvant therapy for GM and nearly half of GM tumors harbor p53 mutations, we sought to identify genes that mediate p53-independent apoptosis of GM cells in response to ionizing radiation. Using broad-scale gene expression analysis we found that following radiation treatment, TRADD expression was induced in a uniquely radiosensitive GM cell line but not in radioresistant GM cell lines. TRADD over-expression killed GM cells and activated NF-κB. We found that blocking the TRADD-mediated pathway using a dominant-negative mutant of FADD (FADD-DN) enhanced radiation resistance of GM cells, as reflected in both susceptibility to apoptosis and clonogenic survival following irradiation. Conversely, stable expression of exogenous TRADD enhanced radiation-induced apoptosis of GM cell lines, reflecting the biological significance of TRADD regulation in p53-independent apoptosis. These findings generate interest in utilizing TRADD in gene therapy for GM tumors, particularly in light of its dual function of directly inducing rapid apoptosis and sensitizing GM cells to standard anti-neoplastic therapy.
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Acknowledgements
We gratefully acknowledge Drs David Stokoe, Osamu Tetsu, Peter Sabbatini and Alexander Gottschalk for their valuable comments and discussion. We thank DV Geoddel for the pRK-TRADD plasmid, VM Dixit for the pcDNA3-FADD-DN plasmid, and P Rodriguez-Viciana for the pBabeHygro retroviral vector. This work was supported by NIH grant M01 RR01271, Pediatric Clinical Research Center, (D Haas-Kogan) and a Pfizer Scholar Grants for New Faculty (D Haas-Kogan).
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Yount, G., Afshar, G., Ries, S. et al. Transcriptional activation of TRADD mediates p53-independent radiation-induced apoptosis of glioma cells. Oncogene 20, 2826–2835 (2001). https://doi.org/10.1038/sj.onc.1204393
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DOI: https://doi.org/10.1038/sj.onc.1204393
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