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.
Highlights
Nasopharyngeal carcinoma (NPC) is sensitive to radiotherapy and chemotherapy, distant metastasis is the primary cause of treatment failure.[4,5]
Kaplan–Meier survival curves and log-rank tests revealed that NEDD8 overexpression levels were significantly correlated with overall survival (OS) and disease-free survival (DFS) in NPC patients (Figures 1b and c)
We confirmed that NEDD8 could be a novel oncogene, and MLN4924 is a promising therapeutic agent for NPC
Summary
Nasopharyngeal carcinoma (NPC) is an endemic malignancy with a high incidence rate in southern China and Southeast Asia.[1,2,3] NPC is sensitive to radiotherapy and chemotherapy, distant metastasis is the primary cause of treatment failure.[4,5] Despite identification of several key molecules driving NPC metastasis in our previous studies,[6,7,8,9,10] the molecular mechanisms underlying NPC progression and metastasis are not fully understood. MLN4924 is a selective NAE inhibitor that has been reported to be a promising anticancer drug candidate.[15] In cellular and animal models of lymphoma, colorectal cancer, liver cancer, pancreatic carcinoma, bladder urothelial carcinoma and breast cancer, MLN4924 has been shown to inhibit tumor cell proliferation and metastasis.[16,17,18,19,20,21] MLN4924 has been reported to enhance p21-dependent radio-sensitization in human breast cancer cells and suppress tumor angiogenesis.[21,22] To date, the detailed mechanisms of NEDD8 and its inhibitor MLN4924 in human NPC remains unknown. Cancer stem cells (CSCs), which make up a small proportion of tumor cells, have a key role in tumor initiation, recurrence and metastasis.[23,24] CSCs have been considered important therapeutic targets for anticancer treatments. We explored the role of NEDD8 in NPC growth, drug resistance and stemness characteristics, as well as evaluated the therapeutic efficacy of MLN4924 in NPC
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