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Suppression of glioblastoma by targeting the overactivated protein neddylation pathway
Wei Hua1, Chunjie Li1, Zixiao Yang1
1Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China (W.H., Z.Y., W.Z., Z.L., Y.M.); Cancer Institute, Fudan University Shanghai Cancer Center; Collaborative Innovation Center of Cancer Medicine; and Department of Oncology, Shanghai Medical College, Shanghai, China (W.H., C.L., L.L., Y.J., G.Y., L.J.); Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China (C.L., Y.J., G.Y., Y.C.); Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (S.D.); AntiCancer Biotech Beijing Co. Ltd., Beijing, China (M.Y.); Shanghai Shines Clinical Laboratories, Inc., The Research base of MDT, DCMST, Ministry of Health, Shanghai, China (Y.Z.); The Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China (Y.M.).
Background:
The neddylation pathway has been recently identified as an attractive anticancer target, and MLN4924, a specific NEDD8-activating enzyme inhibitor, has been developed as a first-in-class anticancer agent. However, neither the status of the neddylation pathway in glioblastoma (GBM) nor the effect of MLN4924 against GBM has been systematically investigated yet.
Methods:
To measure the activation state of the neddylation pathway in GBM, expression of the NEDD8-activating enzyme (E1), NEDD8-conjugating enzyme (E2), and global protein neddylation in GBM tumor tissues versus adjacent tissues were examined by immunoblotting analysis and immunohistochemistry staining. To assess the therapeutic efficacy of neddylation inhibition in GBM, cell proliferation in vitro and tumor growth in vivo were determined upon neddylation inhibition by MLN4924, an investigational NEDD8-activating enzyme inhibitor.
Results:
The neddylation pathway was overactivated in a majority of GBM tumor tissues when compared with adjacent normal tissues. The upregulation of this pathway in GBM tissues was positively correlated with high-grade disease and postoperative recurrence but was negatively associated with patient overall survival. MLN4924 treatment inhibited cullin neddylation, inactivated cullin-RING E3 ligase, and led to the accumulation of tumor-suppressive cullin-RING E3 ligase substrates to trigger cell-cycle arrest and senescence or apoptosis in a cell-line dependent manner. Moreover, inhibition of neddylation by MLN4924 significantly suppressed tumor growth in an orthotopic xenograft model of human GBM.
Conclusion:
Our study indicates that an overactivated neddylation pathway may be involved in GBM progression and that inhibition of this oncogenic pathway is a potentially new therapeutic approach for GBM.
Insights
The neddylation pathway is overactivated in glioblastoma (GBM), driving tumor progression. Inhibiting this pathway with MLN4924 suppressed GBM growth, suggesting a new therapeutic strategy for this aggressive cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The neddylation pathway is a novel anticancer target.
- MLN4924 is a first-in-class NEDD8-activating enzyme inhibitor.
- The role of neddylation in glioblastoma (GBM) remains under-investigated.
Purpose of the Study:
- To investigate the neddylation pathway's status in GBM.
- To evaluate the therapeutic efficacy of MLN4924 in GBM.
Main Methods:
- Immunoblotting and immunohistochemistry to assess neddylation markers in GBM tissues.
- In vitro proliferation assays and in vivo xenograft models to test MLN4924 efficacy.
Main Results:
- Neddylation pathway is overactivated in most GBM tissues, correlating with disease grade and recurrence.
- MLN4924 inhibited neddylation, induced cell-cycle arrest/apoptosis, and suppressed tumor growth in vivo.
- Neddylation inhibition triggered accumulation of tumor-suppressive substrates.
Conclusions:
- Overactivated neddylation pathway is implicated in GBM progression.
- Targeting the neddylation pathway with MLN4924 shows therapeutic potential for GBM.
