Inhibition of Proteasomal Deubiquitinase by Silver Complex Induces Apoptosis in Non-Small Cell Lung Cancer Cells
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 ta...
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| Format: | Article |
| Language: | English |
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Cell Physiol Biochem Press GmbH & Co KG
2018-08-01
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| Series: | Cellular Physiology and Biochemistry |
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| Online Access: | https://www.karger.com/Article/FullText/493041 |
| _version_ | 1819083684883464192 |
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| author | Xin Chen Qianqian Yang Jinghong Chen Peiquan Zhang Qingtian Huang Xiaolan Zhang Li Yang Dacai Xu Chong Zhao Xuejun Wang Jinbao Liu |
| author_facet | Xin Chen Qianqian Yang Jinghong Chen Peiquan Zhang Qingtian Huang Xiaolan Zhang Li Yang Dacai Xu Chong Zhao Xuejun Wang Jinbao Liu |
| author_sort | Xin Chen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T20:36:29Z |
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| institution | Directory Open Access Journal |
| issn | 1015-8987 1421-9778 |
| language | English |
| last_indexed | 2024-12-21T20:36:29Z |
| publishDate | 2018-08-01 |
| publisher | Cell Physiol Biochem Press GmbH & Co KG |
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| series | Cellular Physiology and Biochemistry |
| spelling | doaj.art-fbb04df17ff54b529ec415672a1ba0b42022-12-21T18:51:05ZengCell Physiol Biochem Press GmbH & Co KGCellular Physiology and Biochemistry1015-89871421-97782018-08-0149278079710.1159/000493041493041Inhibition of Proteasomal Deubiquitinase by Silver Complex Induces Apoptosis in Non-Small Cell Lung Cancer CellsXin ChenQianqian YangJinghong ChenPeiquan ZhangQingtian HuangXiaolan ZhangLi YangDacai XuChong ZhaoXuejun WangJinbao LiuBackground/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.https://www.karger.com/Article/FullText/493041ProteasomeDeubiquitinasesSilver complexApoptosisLung cancer |
| spellingShingle | Xin Chen Qianqian Yang Jinghong Chen Peiquan Zhang Qingtian Huang Xiaolan Zhang Li Yang Dacai Xu Chong Zhao Xuejun Wang Jinbao Liu Inhibition of Proteasomal Deubiquitinase by Silver Complex Induces Apoptosis in Non-Small Cell Lung Cancer Cells Cellular Physiology and Biochemistry Proteasome Deubiquitinases Silver complex Apoptosis Lung cancer |
| title | Inhibition of Proteasomal Deubiquitinase by Silver Complex Induces Apoptosis in Non-Small Cell Lung Cancer Cells |
| title_full | Inhibition of Proteasomal Deubiquitinase by Silver Complex Induces Apoptosis in Non-Small Cell Lung Cancer Cells |
| title_fullStr | Inhibition of Proteasomal Deubiquitinase by Silver Complex Induces Apoptosis in Non-Small Cell Lung Cancer Cells |
| title_full_unstemmed | Inhibition of Proteasomal Deubiquitinase by Silver Complex Induces Apoptosis in Non-Small Cell Lung Cancer Cells |
| title_short | Inhibition of Proteasomal Deubiquitinase by Silver Complex Induces Apoptosis in Non-Small Cell Lung Cancer Cells |
| title_sort | inhibition of proteasomal deubiquitinase by silver complex induces apoptosis in non small cell lung cancer cells |
| topic | Proteasome Deubiquitinases Silver complex Apoptosis Lung cancer |
| url | https://www.karger.com/Article/FullText/493041 |
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