The Nedd8-activating enzyme inhibitor MLN4924 (TAK-924/Pevonedistat) induces apoptosis via c-Myc-Noxa axis in head and neck squamous cell carcinoma.
Apoptosis
/ drug effects
Cell Cycle Checkpoints
/ drug effects
Cell Line, Tumor
Cyclopentanes
/ pharmacology
Enzyme Inhibitors
/ pharmacology
Head and Neck Neoplasms
/ drug therapy
Humans
NEDD8 Protein
/ agonists
Proto-Oncogene Proteins c-bcl-2
/ metabolism
Proto-Oncogene Proteins c-myc
/ metabolism
Pyrimidines
/ pharmacology
Signal Transduction
/ drug effects
Squamous Cell Carcinoma of Head and Neck
/ drug therapy
Journal
Cell proliferation
ISSN: 1365-2184
Titre abrégé: Cell Prolif
Pays: England
ID NLM: 9105195
Informations de publication
Date de publication:
Mar 2019
Mar 2019
Historique:
received:
27
03
2018
revised:
08
07
2018
accepted:
25
07
2018
pubmed:
21
10
2018
medline:
16
4
2019
entrez:
21
10
2018
Statut:
ppublish
Résumé
The present study aimed to reveal expression status of the neddylation enzymes in HNSCC and to elucidate the anticancer efficacy and the underlying mechanisms of inhibiting neddylation pathway. The expression levels of neddylation enzymes were estimated by Western blotting in human HNSCC specimens and bioinformatics analysis of the cancer genome atlas (TCGA) database. Cell apoptosis was evaluated by Annexin V fluorescein isothiocyanate/propidium iodide (Annexin V-FITC/PI) stain and fluorescence-activated cell sorting (FACS). Small interfering RNA (siRNA) and the CRISPR-Cas9 system were used to elucidate the underlying molecular mechanism of MLN4924-induced HNSCC apoptosis. Expression levels of NAE1 and UBC12 were prominently higher in HNSCC tissues than that in normal tissues. Inactivation of the neddylation pathway significantly inhibited malignant phenotypes of HNSCC cells. Mechanistic studies revealed that MLN4924 induced the accumulation of CRL ligase substrate c-Myc that transcriptionally activated pro-apoptotic protein Noxa, which triggered apoptosis in HNSCC. These findings determined the over-expression levels of neddylation enzymes in HNSCC and revealed novel mechanisms underlying neddylation inhibition induced growth suppression in HNSCC cells, which provided preclinical evidence for further clinical evaluation of neddylation inhibitors (eg, MLN4924) for the treatment of HNSCC.
Identifiants
pubmed: 30341788
doi: 10.1111/cpr.12536
pmc: PMC6496207
doi:
Substances chimiques
Cyclopentanes
0
Enzyme Inhibitors
0
NEDD8 Protein
0
NEDD8 protein, human
0
PMAIP1 protein, human
0
Proto-Oncogene Proteins c-bcl-2
0
Proto-Oncogene Proteins c-myc
0
Pyrimidines
0
pevonedistat
S3AZD8D215
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e12536Subventions
Organisme : Program of Shanghai Academic/Technology Research Leader
ID : 18XD1403800
Organisme : The Chinese Minister of Science and Technology grant
ID : 2016YFA0501800
Organisme : National Thirteenth Five-Year Science and Technology Major Special Project for New Drug and Development
ID : 2017ZX09304001
Organisme : National Natural Science Foundation of China
ID : 81625018
Organisme : National Natural Science Foundation of China
ID : 81820108022
Organisme : National Natural Science Foundation of China
ID : 81572340
Organisme : National Natural Science Foundation of China
ID : 81772470
Organisme : National Natural Science Foundation of China
ID : 81602072
Organisme : National Natural Science Foundation of China
ID : 81401893
Informations de copyright
© 2018 The Authors. Cell Proliferation published by John Wiley & Sons Ltd.
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