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

Abstract

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.

Synthetic Lethality Screening Highlights Colorectal Cancer Vulnerability to Concomitant Blockade of NEDD8 and EGFR Pathways

“…Differently, in RAS/RAF WT models resistant to EGFR inhibition, pevonedistat had no major effects on the EGFR pathway, as previously reported for glioblastoma [31] and human myeloma [32]. In this case, the cooperation between pevonedistat and EGFR pathway blockade could be ascribed to parallel actions leading to cell death and inhibition of proliferation.…”

Role of Ubiquitination in PTEN Cellular Homeostasis and Its Implications in GB Drug Resistance

“…Inhibitors of oncogenic E3 ligases and other signaling pathways (e.g., the PI3K/AKT/mTOR and Wnt/β-catenin signaling pathways) can be combined to design an effective therapeutic intervention, particularly for the chemotherapy-resistant GB. MLN4924, a NEDD8-activating enzyme inhibitor, blocks ERK and AKT phosphorylation in numerous patient-derived GB stem cells ( 185 ). The focal adhesion kinase inhibitor PF-573228 also enhanced p27/CDKN1B levels and β-galactosidase activity and inhibited the autophagy cargo receptor p62/SQSTM-1.…”

Extracellular Vesicles Derived from Glioblastoma Promote Proliferation and Migration of Neural Progenitor Cells via PI3K-Akt Pathway

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