MEK-ERK Signaling Dictates DNA-Repair Gene MGMT Expression and Temozolomide Resistance of Stem-Like Glioblastoma Cells via the MDM2-p53 Axis
MEK-ERK Signaling Dictates DNA-Repair Gene MGMT Expression and Temozolomide Resistance of Stem-Like Glioblastoma Cells via the MDM2-p53 Axis
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DOI：
10.1002/stem.753
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发表时间：
2011-12-01
期刊：
影响因子：
5.2
通讯作者：
Kitanaka, Chifumi
中科院分区：
文献类型：
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作者：
Sato, Atsushi;Sunayama, Jun;Kitanaka, Chifumi
克服胶质母细胞瘤细胞对替莫唑胺（新诊断的胶质母细胞瘤首选的一线化疗药物）的耐药性是治疗这种致命脑肿瘤的主要治疗挑战。编码 O(6)-甲基鸟嘌呤 DNA 甲基转移酶 (MGMT) 的基因可去除替莫唑胺附着的甲基，在胶质母细胞瘤中经常因启动子甲基化而沉默，但在相当一部分病例中仍表达，因此被认为是临床上最相关的替莫唑胺耐药机制之一。然而，迄今为止，在表达 MGMT 的胶质母细胞瘤细胞中调节 MGMT 的信号通路尚不清楚。在这项研究中，我们提供了一系列证据，证明丝裂原激活蛋白/细胞外信号调节激酶激酶（MEK）-细胞外信号调节激酶（ERK）-小鼠双分钟2（MDM2）-p53通路在MGMT表达的调节中发挥着关键作用，使用直接源自患者肿瘤样本并在不存在的情况下维持的干样胶质母细胞瘤细胞 血清不仅具有干细胞样特性，而且还可以复制其来源的原始肿瘤的特征。我们发现，在干细胞样胶质母细胞瘤细胞中，MEK 抑制降低了 MDM2 的表达，并且 MEK 或 MDM2 的抑制导致 p53 激活，并伴随着 p53 依赖性的 MGMT 表达下调。 MEK 抑制使原本具有耐药性的干细胞样胶质母细胞瘤细胞对替莫唑胺敏感，而 MEK 抑制剂和替莫唑胺联合治疗有效地剥夺了干细胞样胶质母细胞瘤细胞的致瘤潜力。我们的研究结果表明，靶向 MEK-ERK-MDM2-p53 通路与替莫唑胺联合可能是治疗胶质母细胞瘤的一种新颖且有前途的治疗策略。干细胞 2011;29:1942-1951
Overcoming the resistance of glioblastoma cells against temozolomide, the first-line chemotherapeutic agent of choice for newly diagnosed glioblastoma, is a major therapeutic challenge in the management of this deadly brain tumor. The gene encoding O(6)-methylguanine DNA methyltransferase (MGMT), which removes the methyl group attached by temozolomide, is often silenced by promoter methylation in glioblastoma but is nevertheless expressed in a significant fraction of cases and is therefore regarded as one of the most clinically relevant mechanisms of resistance against temozolomide. However, to date, signaling pathways regulating MGMT in MGMT-expressing glioblastoma cells have been poorly delineated. Here in this study, we provide lines of evidence that the mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-extracellular signal-regulated kinase (ERK)-murine double minute 2 (MDM2)-p53 pathway plays a critical role in the regulation of MGMT expression, using stem-like glioblastoma cells directly derived from patient tumor samples and maintained in the absence of serum, which not only possess stem-like properties but are also known to phenocopy the characteristics of the original tumors from which they are derived. We show that, in stem-like glioblastoma cells, MEK inhibition reduced MDM2 expression and that inhibition of either MEK or MDM2 resulted in p53 activation accompanied by p53-dependent downregulation of MGMT expression. MEK inhibition rendered otherwise resistant stem-like glioblastoma cells sensitive to temozolomide, and combination of MEK inhibitor and temozolomide treatments effectively deprived stem-like glioblastoma cells of their tumorigenic potential. Our findings suggest that targeting of the MEK-ERK-MDM2-p53 pathway in combination with temozolomide could be a novel and promising therapeutic strategy in the treatment of glioblastoma. STEM CELLS 2011;29:1942-1951