Inhibition of Proteasomal Deubiquitinase by Silver Complex Induces Apoptosis in Non-Small Cell Lung Cancer Cells
| Autor: | Dacai Xu, Xin Chen, Peiquan Zhang, Chong Zhao, Jinbao Liu, Xuejun Wang, Li Yang, Qianqian Yang, Xiaolan Zhang, Qingtian Huang, Jinghong Chen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Proteasome Endopeptidase Complex Lung Neoplasms Silver Physiology Mice Nude Antineoplastic Agents Apoptosis lcsh:Physiology Deubiquitinating enzyme Flow cytometry lcsh:Biochemistry Mice 03 medical and health sciences Silver complex Western blot Coordination Complexes In vivo Deubiquitinases Carcinoma Non-Small-Cell Lung Cell Line Tumor Disulfiram medicine Animals Humans lcsh:QD415-436 Viability assay Mice Inbred BALB C Deubiquitinating Enzymes biology medicine.diagnostic_test Proteasome lcsh:QP1-981 Chemistry Drug Synergism 030104 developmental biology Caspases biology.protein Cancer research Poly(ADP-ribose) Polymerases Lung cancer Reactive Oxygen Species Intracellular |
| Zdroj: | Cellular Physiology and Biochemistry, Vol 49, Iss 2, Pp 780-797 (2018) |
| ISSN: | 1421-9778 1015-8987 |
| Popis: | Background/Aims: The ubiquitin proteasome system (UPS) is responsible for the degradation of most intracellular proteins, and proteasomal deubiquitinases (DUBs) have recently been highlighted as novel anticancer targets. It is well documented that copper complexes can inhibit UPS function through targeting both 20S proteasome and proteasomal DUBs. The antineoplastic activities of silver complexes have received much attention, but the exact mechanisms are not fully elucidated. In this study, we aim to investigate the effects of a novel silver complex [Ag(S2CN(C2H5)2)]6 (AgDT) on UPS function and its anticancer potential in non-small cell lung cancer (NSCLC). Methods: Cell viability assay (i.e., the MTS assay) and flow cytometry assay were used to analyze the cell viability and apoptosis. Proteasome inhibition was measured using 20S proteasome activity assay and 19S proteasomal DUBs activity assay. Western blot analysis and immunohistochemistry were performed to detect protein levels. The in vivo antitumor activity of AgDT was assessed with nude xenografts. Results: Silver ions, alone or in combination with disulfiram (DSF), induced UPS inhibition in NSCLC cells mainly through inhibition of proteasomal DUBs activities. Silver complex AgDT triggered intracellular accumulation of ubiquitinated proteins, and prevented the degradation of surrogate substrate GFPu. Mechanistically, AgDT potently inhibited the activities of proteasomal DUBs USP14 and UCHL5, without altering the 20S proteasome peptidases. Moreover, AgDT induced apoptosis in NSCLC cells and significantly inhibited tumor growth in xenografts. Conclusion: Our findings suggest that silver complex AgDT is a novel metal-based proteasomal DUBs inhibitor, and pharmacologic inhibition of USP14 and UCHL5 could prove to be an effective therapeutic strategy for NSCLC. |
| Databáze: | OpenAIRE |
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