Proteasome mediated degradation of CDC25C and Cyclin B1 in Demethoxycurcumin treated human glioma U87 MG cells to trigger G2/M cell cycle arrest
Autor: | Neetika Lal, Pratibha Mehta Luthra, Vishal Nemaysh |
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Rok vydání: | 2018 |
Předmět: |
G2 Phase
0301 basic medicine Proteasome Endopeptidase Complex Curcumin Cell cycle checkpoint Toxicology 03 medical and health sciences 0302 clinical medicine Diarylheptanoids Cell Line Tumor Glioma CDC2 Protein Kinase medicine Humans cdc25 Phosphatases Cyclin B1 Protein kinase B Pharmacology chemistry.chemical_classification Reactive oxygen species Cyclin-dependent kinase 1 Cell Cycle Checkpoints medicine.disease Cell biology Molecular Docking Simulation 030104 developmental biology chemistry Proteasome Apoptosis 030220 oncology & carcinogenesis Reactive Oxygen Species Cell Division |
Zdroj: | Toxicology and Applied Pharmacology. 356:76-89 |
ISSN: | 0041-008X |
Popis: | Recently, we have reported that Demethoxycurcumin induced Reactive oxygen species via inhibition of Mitochondrial Superoxide Dismutase is an initial event to trigger apoptosis through caspase-8 and 9 activation and to inhibit Akt/NF-κB survival signaling in human glioma U87 MG cells (Kumar et al., 2018). Although cell-cycle disruption had been suggested to be the possible mechanism for DMC inhibitory effect on human glioma U87 MG cells, comprehensive mechanisms of cell-cycle arrest caused by DMC are not fully understood. The present study was designed to elucidate the DMC induced mechanism of cell cycle arrest in human glioma U87 MG cells. In this study, the results illustrated that DMC induced Reactive oxygen species (ROS) leads to reduced expression of CDC25C, Cyclin B1 and CDK1 (Thr161) triggers G2/M cell cycle arrest in U87 MG glioma cells. Moreover, the DMC induced ROS generation activates ubiquitination and proteasome degradation of CDC25C and Cyclin B1 in U87MG glioma cells. In addition, the immunoprecipitation results showed that significant dissociation of CDK1or CDC2-Cyclin B1 complex leads to G2/M cell cycle arrest. To explore the possibility of direct involvement of DMC in the dissociation of CDK1/Cyclin B1 complex, the molecular docking and MD simulation studies were carried. The results showed that DMC nicely fitted into the binding site of CDK1 and Cyclin B1 with minimum binding energy (ΔG) of -9.46 kcal/mol (Ki = 0.11 μM) and − 9.90 kcal/mol (Ki = 0.05 μM) respectively. Therefore, this is the first study demonstrating CDC25C and Cyclin B1 proteins could be used as potential target for anticancer therapy and DMC may be explored as new therapeutic agent in the cure of Glioblastoma (GBM). |
Databáze: | OpenAIRE |
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