The Protein Neddylation Inhibitor MLN4924 Suppresses Patient-Derived Glioblastoma Cells via Inhibition of ERK and AKT Signaling
The Protein Neddylation Inhibitor MLN4924 Suppresses Patient-Derived Glioblastoma Cells via Inhibition of ERK and AKT Signaling
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DOI：
10.3390/cancers11121849
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发表时间：
2019-12-01
期刊：
影响因子：
5.2
通讯作者：
Nam, Do-Hyun
中科院分区：
文献类型：
--
作者：
Han, Suji;Shin, Hyemi;Nam, Do-Hyun
胶质母细胞瘤是一种高度侵袭性和致命的脑肿瘤，治疗选择有限。在胶质母细胞瘤中观察到neddylation途径的异常激活，并且NEDD 8激活酶（NAE）抑制剂MLN 4924先前已在胶质母细胞瘤细胞系模型中显示有效。然而，其效果尚未在患者来源的胶质母细胞瘤干细胞中进行测试。我们首先分析了公开数据，以确定NEDD 8通路蛋白在胶质母细胞瘤的发展和患者生存中是否重要。NAE 1和UBA 3水平在胶质母细胞瘤患者中升高;高NEDD 8水平与不良临床结局相关。免疫组化结果也支持这一结果。使用高含量分析在4种胶质母细胞瘤细胞系和15种患者源性胶质母细胞瘤干细胞中评价了MLN 4924的作用。胶质母细胞瘤细胞系和患者源性干细胞对MLN 4924高度敏感，而正常人星形胶质细胞具有耐药性。此外，MLN 4924处理后，15例患者源性胶质母细胞瘤干细胞中存在各种缓解。基因组分析表明，MLN 4924敏感细胞显示出细胞外信号调节激酶（ERK）和蛋白激酶B（AKT，也称为PK B）信号转导富集。我们验证了MLN 4924可抑制MLN 4924敏感细胞中的ERK和AKT磷酸化。我们的研究结果表明，在ERK和AKT激活的背景下，患者来源的胶质母细胞瘤干细胞是敏感的，并受到neddylation抑制的高度调节。
Glioblastoma is a highly aggressive and lethal brain tumor, with limited treatment options. Abnormal activation of the neddylation pathway is observed in glioblastoma, and the NEDD8-activating enzyme (NAE) inhibitor, MLN4924, was previously shown to be effective in glioblastoma cell line models. However, its effect has not been tested in patient-derived glioblastoma stem cells. We first analyzed public data to determine whether NEDD8 pathway proteins are important in glioblastoma development and patient survival. NAE1 and UBA3 levels increased in glioblastoma patients; high NEDD8 levels were associated with poor clinical outcomes. Immunohistochemistry results also supported this result. The effects of MLN4924 were evaluated in 4 glioblastoma cell lines and 15 patient-derived glioblastoma stem cells using high content analysis. Glioblastoma cell lines and patient-derived stem cells were highly susceptible to MLN4924, while normal human astrocytes were resistant. In addition, there were various responses in 15 patient-derived glioblastoma stem cells upon MLN4924 treatment. Genomic analyses indicated that MLN4924 sensitive cells exhibited enrichment of Extracellular Signal Regulated Kinase (ERK) and Protein kinase B (AKT, also known as PKB) signaling. We verified that MLN4924 inhibits ERK and AKT phosphorylation in MLN4924 sensitive cells. Our findings suggest that patient-derived glioblastoma stem cells in the context of ERK and AKT activation are sensitive and highly regulated by neddylation inhibition.