EFEMP1 induces γ-secretase/Notch-mediated temozolomide resistance in glioblastoma.
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.
Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.
Lotte
L
Hiddingh
Bakhos A
BA
Tannous
Jian
J
Teng
Bas
B
Tops
Judith
J
Jeuken
Esther
E
Hulleman
Sandra H
SH
Boots-Sprenger
W Peter
WP
Vandertop
David P
DP
Noske
Gertjan J L
GJ
Kaspers
Pieter
P
Wesseling
Thomas
T
Wurdinger
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000077204:Temozolomide; D014162:Transfection; D005466:Fluorocarbons
D053829:Amyloid Precursor Protein Secretases; D018906:Antineoplastic Agents, Alkylating; D001552:Benzazepines; D003606:Dacarbazine; D016326:Extracellular Matrix Proteins; D051880:Receptors, Notch; D000077204:Temozolomide; C119630:EFEMP1 protein, human; C545185:2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide; D005466:Fluorocarbons