Interferon-β induces loss of spherogenicity and overcomes therapy resistance of glioblastoma stem cells
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Interferon-β induces loss of spherogenicity and overcomes therapy resistance of glioblastoma stem cells. / Happold, Caroline; Roth, Patrick; Silginer, Manuela; Florea, Ana-Maria; Lamszus, Katrin; Frei, Karl; Deenen, Rene; Reifenberger, Guido; Weller, Michael.
in: MOL CANCER THER, Jahrgang 13, Nr. 4, 2014, S. 948-961.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Interferon-β induces loss of spherogenicity and overcomes therapy resistance of glioblastoma stem cells
AU - Happold, Caroline
AU - Roth, Patrick
AU - Silginer, Manuela
AU - Florea, Ana-Maria
AU - Lamszus, Katrin
AU - Frei, Karl
AU - Deenen, Rene
AU - Reifenberger, Guido
AU - Weller, Michael
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - Antineoplastic Agents
KW - Cell Cycle
KW - Cell Line, Tumor
KW - Dacarbazine
KW - Drug Resistance, Neoplasm
KW - Gene Expression Regulation, Neoplastic
KW - Glioblastoma
KW - Humans
KW - Interferon-beta
KW - K562 Cells
KW - MCF-7 Cells
KW - Molecular Sequence Data
KW - Neoplastic Stem Cells
KW - Receptor, Interferon alpha-beta
KW - Signal Transduction
U2 - 10.1158/1535-7163.MCT-13-0772
DO - 10.1158/1535-7163.MCT-13-0772
M3 - SCORING: Journal article
C2 - 24526161
VL - 13
SP - 948
EP - 961
JO - MOL CANCER THER
JF - MOL CANCER THER
SN - 1535-7163
IS - 4
ER -