Nedd8-activating enzyme inhibitor MLN4924 (Pevonedistat), inhibits miR-1303 to suppress human breast cancer cell proliferation via targeting p27Kip1.

Abstract

MLN4924/Pevonedistat, a Nedd8-activating enzyme (NAE, E1) inhibitor, has shown notable anti-cancer effect in pre-clinical trials, but it still faces tolerance resistance risk. Combination target therapy indicates a much better clinical effect than single target, and miRNAs are beneficial for easy detection in bodily fluids and tissues. Up to now, MLN4924 and miRNA-targeting combination approaching to treat breast cancer patients remains largely unknown. Here, microRNA-seq analysis showed that the expression of miR-1303 was significantly decreased after MLN4924 treatment in breast cancer cells. Moreover, miR-1303 was abnormally high in breast cancer tissues, and breast cancer patients with high miR-1303 showed poor prognosis. Functionally, excessive miR-1303 promoted the malignant phenotypes of breast cancer cells. Excessive miR-1303 accelerated cell cycle progression by promoting G2/M arrest. Furthermore, we revealed that miR-1303 targeted p27Kip1 to release G2/M arrest. Notably, excessive miR-1303 partially disturbed the anti-cancer effect of MLN4924. These findings provide potential evidences for combined anti-cancer target therapy of breast cancer patients in the future.

• Authors: Yujiao Chen, Mengge Du, Shadamu Yusuying, Wei Liu, Yawen Tan, Ping Xie
• Journal: Experimental cell research (Exp Cell Res) Vol. 392 Issue 2 Pg. 112038 (07 15 2020) ISSN: 1090-2422 [Electronic] United States
• PMID: 32360865 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers, Tumor
• CDKN1B protein, human
• Cyclopentanes
• Enzyme Inhibitors
• MIRN1303 microRNA, human
• MicroRNAs
• NEDD8 Protein
• NEDD8 protein, human
• Pyrimidines
• Cyclin-Dependent Kinase Inhibitor p27
• Ubiquitin-Activating Enzymes
• NAE protein, human
• pevonedistat

Topics

• Apoptosis
• Biomarkers, Tumor
• Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• Cell Cycle
• Cell Proliferation
• Cyclin-Dependent Kinase Inhibitor p27 (genetics, metabolism)
• Cyclopentanes (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• MicroRNAs (genetics)
• NEDD8 Protein (genetics, metabolism)
• Prognosis
• Pyrimidines (pharmacology)
• Survival Rate
• Tumor Cells, Cultured
• Ubiquitin-Activating Enzymes (antagonists & inhibitors, genetics, metabolism)