TY - JOUR
T1 - EFEMP1 induces γ-secretase/Notch-mediated temozolomide resistance in glioblastoma
AU - Hiddingh, Lotte
AU - Tannous, Bakhos A.
AU - Teng, Jian
AU - Tops, Bas
AU - Jeuken, Judith
AU - Hulleman, Esther
AU - Boots-Sprenger, Sandra H.
AU - Vandertop, W. Peter
AU - Noske, David P.
AU - Kaspers, Gertjan J. L.
AU - Wesseling, Pieter
AU - Wurdinger, Thomas
PY - 2014
Y1 - 2014
N2 - Glioblastoma is the most common malignant primary brain tumor. Temozolomide (TMZ) is the standard chemotherapeutic agent for this disease. However, intrinsic and acquired TMZ-resistance represents a major obstacle for this therapy. In order to identify factors involved in TMZ-resistance, we engineered different TMZ-resistant glioblastoma cell lines. Gene expression analysis demonstrated that EFEMP1, an extracellular matrix protein, is associated with TMZ-resistant phenotype. Silencing of EFEMP1 in glioblastoma cells resulted in decreased cell survival following TMZ treatment, whereas overexpression caused TMZ-resistance. EFEMP1 acts via multiple signaling pathways, including γ-secretase-mediated activation of the Notch pathway. We show that inhibition of γ-secretase by RO4929097 causes at least partial sensitization of glioblastoma cells to temozolomide in vitro and in vivo. In addition, we show that EFEMP1 expression levels correlate with survival in TMZ-treated glioblastoma patients. Altogether our results suggest EFEMP1 as a potential therapeutic target to overcome TMZ-resistance in glioblastoma
AB - Glioblastoma is the most common malignant primary brain tumor. Temozolomide (TMZ) is the standard chemotherapeutic agent for this disease. However, intrinsic and acquired TMZ-resistance represents a major obstacle for this therapy. In order to identify factors involved in TMZ-resistance, we engineered different TMZ-resistant glioblastoma cell lines. Gene expression analysis demonstrated that EFEMP1, an extracellular matrix protein, is associated with TMZ-resistant phenotype. Silencing of EFEMP1 in glioblastoma cells resulted in decreased cell survival following TMZ treatment, whereas overexpression caused TMZ-resistance. EFEMP1 acts via multiple signaling pathways, including γ-secretase-mediated activation of the Notch pathway. We show that inhibition of γ-secretase by RO4929097 causes at least partial sensitization of glioblastoma cells to temozolomide in vitro and in vivo. In addition, we show that EFEMP1 expression levels correlate with survival in TMZ-treated glioblastoma patients. Altogether our results suggest EFEMP1 as a potential therapeutic target to overcome TMZ-resistance in glioblastoma
U2 - https://doi.org/10.18632/oncotarget.1620
DO - https://doi.org/10.18632/oncotarget.1620
M3 - Article
C2 - 24495907
SN - 1949-2553
VL - 5
SP - 363
EP - 374
JO - Oncotarget
JF - Oncotarget
IS - 2
ER -