Interferon-β induces loss of spherogenicity and overcomes therapy resistance of glioblastoma stem cells

TY - JOUR

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 -