Interferon-β Induces Loss of Spherogenicity and Overcomes Therapy Resistance of Glioblastoma Stem Cells

摘要: Glioblastoma is the most common malignant brain tumor in adults and characterized by a poor prognosis. Glioma cells expressing O(6)-methylguanine DNA methyltransferase (MGMT) exhibit higher level of resistance toward alkylating agents, including standard care chemotherapeutic agent temozolomide. Here, we demonstrate that long-term glioma cell lines (LTL) as well glioma-initiating (GIC) express receptors for immune modulatory cytokine IFN-β respond to with induction STAT-3 phosphorylation. Exposure induces minor loss viability, but strongly interferes sphere formation GIC cultures. Furthermore, sensitizes LTL temozolomide irradiation. RNA interference confirmed both receptors, R1 R2, are required IFN-β-mediated sensitization, sensitization independent MGMT or TP53. Most highly temozolomide-resistant, mediated expression, nevertheless susceptible sensitization. Gene expression profiling following treatment revealed strong upregulation IFN-β-associated genes, proapoptotic gene cluster, did not alter stemness-associated signatures. Caspase activity inhibition studies genes mediate exogenous death ligands IFN-β, irradiation, indicating distinct pathways IFN-β. Thus, potential adjunct glioblastoma may target population. operates independently MGMT-mediated resistance, classical apoptosis-regulatory networks, clusters.