EFEMP1 induces γ-secretase/Notch-mediated temozolomide resistance in glioblastoma

Lotte Hiddingh, Bakhos A. Tannous, Jiang Teng, Bas Tops, Judith Jeuken, Esther Hulleman, Sandra H. Boots-Sprenger, William P. Vandertop, David P. Noske, Gertjan J.L. Kaspers, Pieter Wesseling, Thomas Wurdinger

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

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.
Originele taal-2Engels
Pagina's (van-tot)363-374
TijdschriftOncotarget
Volume5
Nummer van het tijdschrift2
DOI's
StatusGepubliceerd - 30 jan. 2014
Extern gepubliceerdJa

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