Transcriptional activation of TRADD mediates p53-independent radiation-induced apoptosis of glioma cells

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 rega rdless of the therapeutic approach, Since radiation therapy is the most eff ective adjuvant therapy for GM and nearly half of GM tumors harbor p53 muta tions, we sought to identify genes that mediate p53-independent apoptosis o f GM cells in response to ionizing radiation. Using broad-scale gene expres sion analysis we found that following radiation treatment, TRADD expression was induced in a uniquely radiosensitive GM cell line but not in radioresi stant GM cell lines. TRADD over-expression killed GM cells and activated NF -kappaB, We found that blocking the TRADD-mediated pathway using a dominant -negative mutant of FADD (FADD-DN) enhanced radiation resistance of GM cell s, as reflected in both susceptibility to apoptosis and clonogenic survival following irradiation, Conversely stable expression of exogenous TRADD enh anced radiation-induced apoptosis of GM cell lines, reflecting the biologic al significance of TRADD regulation in p53-independent apoptosis, These fin dings generate interest in utilizing TRADD in gene therapy for GM tumors, p articularly in light of its dual function of directly inducing rapid apopto sis and sensitizing GM cells to standard anti-neoplastic therapy.