EFEMP1在胶质母细胞瘤中诱导γ-分泌酶/Notch介导的替莫唑胺耐药。
EFEMP1 induces γ-secretase/Notch-mediated temozolomide resistance in glioblastoma.
作者信息
Hiddingh Lotte, Tannous Bakhos A, Teng Jian, Tops Bas, Jeuken Judith, Hulleman Esther, Boots-Sprenger Sandra H, Vandertop W Peter, Noske David P, Kaspers Gertjan J L, Wesseling Pieter, Wurdinger Thomas
机构信息
Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.
出版信息
Oncotarget. 2014 Jan 30;5(2):363-74. doi: 10.18632/oncotarget.1620.
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.
胶质母细胞瘤是最常见的原发性恶性脑肿瘤。替莫唑胺（TMZ）是治疗该疾病的标准化疗药物。然而，原发性和获得性替莫唑胺耐药是这种治疗方法的主要障碍。为了确定与替莫唑胺耐药相关的因素，我们构建了不同的替莫唑胺耐药胶质母细胞瘤细胞系。基因表达分析表明，细胞外基质蛋白EFEMP1与替莫唑胺耐药表型相关。在胶质母细胞瘤细胞中敲低EFEMP1会导致替莫唑胺处理后细胞存活率降低，而过表达则会导致替莫唑胺耐药。EFEMP1通过多种信号通路发挥作用，包括γ-分泌酶介导的Notch通路激活。我们发现，RO4929097抑制γ-分泌酶可使胶质母细胞瘤细胞在体外和体内至少部分对替莫唑胺敏感。此外，我们还表明，EFEMP1表达水平与接受替莫唑胺治疗的胶质母细胞瘤患者的生存率相关。总之，我们的结果表明EFEMP1是克服胶质母细胞瘤替莫唑胺耐药的潜在治疗靶点。
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