Abstract
Nasopharyngeal carcinoma (NPC), is one of the most common human malignancies in south China, it has the highest recurrence rate and treatment resistance. The underlying molecular mechanisms of NPC relapse and treatment tolerance are not fully understood. In this study, the effects of NEDD8 and NEDD8-activating enzyme inhibitor (MLN4924) on NPC were studied both in vitro and in vivo. Immunohistochemical staining of 197 NPC tissues revealed an elevated NEDD8 expression as an unfavorable independent factor in overall survival and disease-free survival rates. NEDD8 expression was positively correlated with a high risk of death and positivity of lymph node metastasis. Depleted NEDD8 expression by shRNA and inhibited by specific inhibitor MLN4924 dramatically suppressed cell proliferation, cell apoptosis, cell cycle arrest, while ectopic NEDD8 exhibited opposing effects. NEDD8 affected cancer stem cell phenotypes of NPC as assessed in vitro using the cell number of side population (SP) by flow cytometry analysis, colony formation assay, sphere formation assay, and tumor initiation ability in vivo. Downregulation of NEDD8 enhanced the susceptibility of NPC cells to cisplatin and radiation. Moreover, we found that MLN4924 suppressed c-Jun degradation in human NPC cells. Taken together, this report revealed that NEDD8 may act as a novel prognostic marker and MLN4924 may serve as a promising therapeutic target for patients with NPC.
MeSH terms
-
Adult
-
Animals
-
Antineoplastic Agents / therapeutic use
-
Apoptosis / drug effects*
-
Apoptosis / genetics
-
Apoptosis / radiation effects
-
Carcinogenesis / drug effects*
-
Carcinogenesis / genetics
-
Carcinogenesis / pathology
-
Carcinogenesis / radiation effects
-
Carcinoma / genetics
-
Carcinoma / metabolism
-
Carcinoma / pathology
-
Carcinoma / therapy*
-
Cell Cycle Checkpoints / drug effects
-
Cell Cycle Checkpoints / radiation effects
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
Cell Proliferation / radiation effects
-
Cisplatin / therapeutic use
-
Cyclopentanes / therapeutic use*
-
Female
-
Gamma Rays
-
Gene Expression Regulation, Neoplastic*
-
Humans
-
JNK Mitogen-Activated Protein Kinases / genetics
-
JNK Mitogen-Activated Protein Kinases / metabolism
-
Lymphatic Metastasis
-
Male
-
Mice
-
Mice, Nude
-
Middle Aged
-
Molecular Targeted Therapy
-
NEDD8 Protein / antagonists & inhibitors
-
NEDD8 Protein / genetics*
-
NEDD8 Protein / metabolism
-
Nasopharyngeal Carcinoma
-
Nasopharyngeal Neoplasms / genetics
-
Nasopharyngeal Neoplasms / metabolism
-
Nasopharyngeal Neoplasms / pathology
-
Nasopharyngeal Neoplasms / therapy*
-
Neoplastic Stem Cells / drug effects
-
Neoplastic Stem Cells / metabolism
-
Neoplastic Stem Cells / pathology
-
Neoplastic Stem Cells / radiation effects
-
Pyrimidines / therapeutic use*
-
RNA, Small Interfering / genetics
-
RNA, Small Interfering / metabolism
-
Signal Transduction
-
Survival Analysis
-
Xenograft Model Antitumor Assays
Substances
-
Antineoplastic Agents
-
Cyclopentanes
-
NEDD8 Protein
-
NEDD8 protein, human
-
Pyrimidines
-
RNA, Small Interfering
-
JNK Mitogen-Activated Protein Kinases
-
Cisplatin
-
pevonedistat