pevonedistat and Carcinogenesis

Estrogen-related receptor beta (ERRβ) is downregulated in breast cancer cells and its overexpression in breast cancer patients is positively correlated with an improved prognosis and prolonged relapse-free survival. Here, we unravelled a molecular mechanism for ERRβ downregulation in breast cancer. We found that ERRβ is a key substrate of the SCF complex and that NEDDylation can activate the Cullin subunits of the SCF complex to target ERRβ for degradation in breast cancer. Consistently, using in vitro and in vivo models, we demonstrated that MLN4924, a specific small molecule inhibitor of NEDDylation, can restore ERRβ expression and culminate in a reduction in cell proliferation and migration of breast cancer cells. We also showed that increased ERRβ expression promotes the upregulation of its target genes, including the tumour suppressors p21

Topics: Breast Neoplasms; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Cullin Proteins; Cyclopentanes; Disease Progression; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Gene Expression Regulation, Neoplastic; Humans; NEDD8 Protein; Neoplasm Recurrence, Local; Pyrimidines; Receptors, Estrogen; Ubiquitins

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.

Topics: Adult; Animals; Antineoplastic Agents; Apoptosis; Carcinogenesis; Carcinoma; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cisplatin; Cyclopentanes; Female; Gamma Rays; Gene Expression Regulation, Neoplastic; Humans; JNK Mitogen-Activated Protein Kinases; Lymphatic Metastasis; Male; Mice; Mice, Nude; Middle Aged; Molecular Targeted Therapy; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; NEDD8 Protein; Neoplastic Stem Cells; Pyrimidines; RNA, Small Interfering; Signal Transduction; Survival Analysis; Xenograft Model Antitumor Assays