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

// Lotte Hiddingh 1,2,3 , Bakhos A. Tannous 4 , Jian Teng 4 , Bas Tops 5 , Judith Jeuken 5,7 , Esther Hulleman 2,3 , Sandra H. Boots-Sprenger 5 , W. Peter Vandertop 1 , David P. Noske 1,3 , Gertjan J.L. Kaspers 2 , Pieter Wesseling 5,6 , Thomas Wurdinger 1,3,4 1 Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands 2 Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands 3  Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands 4  Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA 5  Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands 6  Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands 7  Department of Pathology, PAMM, Eindhoven, The Netherlands Correspondence: Thomas Wurdinger, email: // Keywords : Temozolomide resistance, glioblastoma, EFEMP1, γ-secretase, Notch, GSI Received : November 20, 2013 Accepted : December 5, 2013 Published : December 7, 2013 Abstract 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.