title: Interferon-β induces loss of spherogenicity and overcomes therapy resistance of glioblastoma stem cells.
abstract: 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 a higher level of resistance toward alkylating agents, including the standard of care chemotherapeutic agent temozolomide. Here, we demonstrate that long-term glioma cell lines (LTL) as well as glioma-initiating cell lines (GIC) express receptors for the immune modulatory cytokine IFN-β and respond to IFN-β with induction of STAT-3 phosphorylation. Exposure to IFN-β induces a minor loss of viability, but strongly interferes with sphere formation in GIC cultures. Furthermore, IFN-β sensitizes LTL and GIC to temozolomide and irradiation. RNA interference confirmed that both IFN-β receptors, R1 and R2, are required for IFN-β-mediated sensitization, but that sensitization is independent of MGMT or TP53. Most GIC lines are highly temozolomide-resistant, mediated by MGMT expression, but nevertheless susceptible to IFN-β sensitization. Gene expression profiling following IFN-β treatment revealed strong upregulation of IFN-β-associated genes, including a proapoptotic gene cluster, but did not alter stemness-associated expression signatures. Caspase activity and inhibition studies revealed the proapoptotic genes to mediate glioma cell sensitization to exogenous death ligands by IFN-β, but not to temozolomide or irradiation, indicating distinct pathways of death sensitization mediated by IFN-β. Thus, IFN-β is a potential adjunct to glioblastoma treatment that may target the GIC population. IFN-β operates independently of MGMT-mediated resistance, classical apoptosis-regulatory networks, and stemness-associated gene clusters.
authors: Authors' Affiliations: Laboratory of Molecular Neuro-Oncology, Department of Neurology, and Department of Neurosurgery, University Hospital Zurich and Neuroscience Center Zurich, Zurich, Switzerland; Laboratory for Brain Tumor Biology, Department of Neurosurgery, University Hospital Hamburg-Eppendorf, Hamburg; Department of Neuropathology and Center for Biological and Medical Research, Heinrich Heine University, Düsseldorf; and German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Caroline
authors: C
authors: Happold
authors: Patrick
authors: P
authors: Roth
authors: Manuela
authors: M
authors: Silginer
authors: Ana-Maria
authors: AM
authors: Florea
authors: Katrin
authors: K
authors: Lamszus
authors: Karl
authors: K
authors: Frei
authors: Rene
authors: R
authors: Deenen
authors: Guido
authors: G
authors: Reifenberger
authors: Michael
authors: M
authors: Weller
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D020014:K562 Cells; D061986:MCF-7 Cells; D008969:Molecular Sequence Data; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D000077204:Temozolomide
chemical_list: D000970:Antineoplastic Agents; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D003606:Dacarbazine; D000077204:Temozolomide