title: Suppression of glioblastoma by targeting the overactivated protein neddylation pathway.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department 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.).
authors.forename: Wei
authors.initials: W
authors.lastname: Hua
authors.affiliation: Department 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.).
authors.forename: Chunjie
authors.initials: C
authors.lastname: Li
authors.affiliation: Department 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.).
authors.forename: Zixiao
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department 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.).
authors.forename: Lihui
authors.initials: L
authors.lastname: Li
authors.affiliation: Department 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.).
authors.forename: Yanan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department 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.).
authors.forename: Guangyang
authors.initials: G
authors.lastname: Yu
authors.affiliation: Department 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.).
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department 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.).
authors.forename: Zhengyan
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department 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.).
authors.forename: Shengzhong
authors.initials: S
authors.lastname: Duan
authors.affiliation: Department 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.).
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Chu
authors.affiliation: Department 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.).
authors.forename: Meng
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department 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.).
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department 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.).
authors.forename: Ying
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department 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.).
authors.forename: Lijun
authors.initials: L
authors.lastname: Jia
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000517:prevention & control; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000378:metabolism; D003517:Cyclopentanes / Q000494:pharmacology* / Q000627:therapeutic use; D018450:Disease Progression; D005909:Glioblastoma / Q000378:metabolism* / Q000401:mortality / Q000517:prevention & control; D006801:Humans; D000075687:NEDD8 Protein; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*; D014452:Ubiquitins / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D044842:Cullin Proteins; D003517:Cyclopentanes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011743:Pyrimidines; D014452:Ubiquitins; C539933:pevonedistat
keywords: MLN4924; NEDD8; cullin-RING E3 ligase; glioblastoma; neddylation