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Open AccessArticle

The Protein Neddylation Inhibitor MLN4924 Suppresses Patient-Derived Glioblastoma Cells via Inhibition of ERK and AKT Signaling

by 1,2, 1, 1,2, 1, 1,* and 1,2,3,*
1
Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea
2
Department of Health Sciences & Technology, Samsung Advanced Institute for Health Science & Technology (SAIHST), Sungkyunkwan University, Seoul 06351, Korea
3
Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University, Seoul 06351, Korea
*
Authors to whom correspondence should be addressed.
Cancers 2019, 11(12), 1849; https://doi.org/10.3390/cancers11121849
Received: 17 October 2019 / Revised: 19 November 2019 / Accepted: 20 November 2019 / Published: 22 November 2019
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. View Full-Text
Keywords: MLN4924; NEDD8; neddylation; glioblastoma MLN4924; NEDD8; neddylation; glioblastoma
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MDPI and ACS Style

Han, S.; Shin, H.; Oh, J.-W.; Oh, Y.J.; Her, N.-G.; Nam, D.-H. The Protein Neddylation Inhibitor MLN4924 Suppresses Patient-Derived Glioblastoma Cells via Inhibition of ERK and AKT Signaling. Cancers 2019, 11, 1849. https://doi.org/10.3390/cancers11121849

AMA Style

Han S, Shin H, Oh J-W, Oh YJ, Her N-G, Nam D-H. The Protein Neddylation Inhibitor MLN4924 Suppresses Patient-Derived Glioblastoma Cells via Inhibition of ERK and AKT Signaling. Cancers. 2019; 11(12):1849. https://doi.org/10.3390/cancers11121849

Chicago/Turabian Style

Han, Suji; Shin, Hyemi; Oh, Jeong-Woo; Oh, Yun J.; Her, Nam-Gu; Nam, Do-Hyun. 2019. "The Protein Neddylation Inhibitor MLN4924 Suppresses Patient-Derived Glioblastoma Cells via Inhibition of ERK and AKT Signaling" Cancers 11, no. 12: 1849. https://doi.org/10.3390/cancers11121849

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