A first-in-class inhibitor, MLN4924 (pevonedistat), induces cell-cycle arrest, senescence, and apoptosis in human renal cell carcinoma by suppressing UBE2M-dependent neddylation modification
| Autor: | Yujun Du, Junliang Chang, Yuyou Deng, Haoran Guo, Bo Xu, Guanchen Liu, Neelam Kumari Shah, Chang Shu, Wei Wei, Ran Bi, Chunxi Wang |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Cell cycle checkpoint Cell Antineoplastic Agents Apoptosis Cyclopentanes Ubiquitin-Activating Enzymes Toxicology 03 medical and health sciences chemistry.chemical_compound Mice Cell Line Tumor medicine Animals Humans Pharmacology (medical) Propidium iodide Clonogenic assay Carcinoma Renal Cell Cellular Senescence Cell Proliferation Pharmacology Mice Inbred BALB C Dose-Response Relationship Drug Cell Cycle Checkpoints Cell cycle Flow Cytometry Xenograft Model Antitumor Assays Kidney Neoplasms 030104 developmental biology medicine.anatomical_structure Pyrimidines Oncology chemistry Cancer cell Ubiquitin-Conjugating Enzymes Cancer research Neddylation DNA Damage |
| Zdroj: | Cancer chemotherapy and pharmacology. 81(6) |
| ISSN: | 1432-0843 |
| Popis: | MLN4924 is a second-generation inhibitor that targets ubiquitin–proteasome system by inhibiting neddylation activation enzyme (NAE), and subsequently blocking the neddylation-dependent activation of Cullin-RING E3 ligases (CRLs), which leads to the accumulation of CRLs substrates and hence, suppressing diverse tumor development. In this study, we investigated the potential application of this first-in-class inhibitor MLN4924 in the treatment of human renal cell carcinoma both in vitro and in vivo. The impact of MLN4924 on renal cancer cells was determined by measuring viability (MTS), proliferation cell count test and clonogenic assays, cell cycle progression (flow cytometry with propidium iodide staining), apoptosis (flow cytometry with annexin V-FITC labeling) and DNA damage (immunofluorescent staining). The cell cycle regulatory molecules, apoptosis-related molecules, and cell stress-related proteins were examined by Western blotting. The influence of tumor cell migration was analyzed by wound healing assays. A well-established SCID xenograft mouse model was used to evaluate the effects of MLN4924 on tumor growth in vivo. The data showed that MLN4924 induced a dose-dependent cytotoxicity, anti-proliferation, anti-migration, and apoptosis in human renal cancer cells; and caused cell cycle arrested at the G2 phase. In addition, the E2 conjugating enzymes of Neddylation UBE2M played a major role in the proliferation control of renal cancer cells. Finally, we confirmed MLN4924 inhibited tumor growth in a RCC xenograft mouse model with minimal general toxicity. We concluded that MLN4924 induces apoptosis and cell cycle arrest. These findings implied that MLN4924 provides a novel strategy for the treatment of RCC. |
| Databáze: | OpenAIRE |
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