Inhibition of Proteasomal Deubiquitinase by Silver Complex Induces Apoptosis in Non-Small Cell Lung Cancer Cells

Xin Chen, Qianqian Yang, Jinghong Chen, Peiquan Zhang, Qingtian Huang, Xiaolan Zhang, Li Yang, Dacai Xu, Chong Zhao, Xuejun Wang, Jinbao Liu

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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(S 2 CN(C 2 H 5 ) 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.

Original languageEnglish (US)
Pages (from-to)780-797
Number of pages18
JournalCellular Physiology and Biochemistry
Volume49
Issue number2
DOIs
StatePublished - Sep 1 2018

Fingerprint

Proteasome Endopeptidase Complex
Silver
Non-Small Cell Lung Carcinoma
Apoptosis
Ubiquitin
Heterografts
Cell Survival
Ubiquitinated Proteins
Disulfiram
Deubiquitinating Enzymes
Antineoplastic Agents
Proteolysis
Copper
Flow Cytometry
Proteins
Peptide Hydrolases
Western Blotting
Metals
Immunohistochemistry
Ions

Keywords

  • Apoptosis
  • Deubiquitinases
  • Lung cancer
  • Proteasome
  • Silver complex

ASJC Scopus subject areas

  • Physiology

Cite this

Inhibition of Proteasomal Deubiquitinase by Silver Complex Induces Apoptosis in Non-Small Cell Lung Cancer Cells. / Chen, Xin; Yang, Qianqian; Chen, Jinghong; Zhang, Peiquan; Huang, Qingtian; Zhang, Xiaolan; Yang, Li; Xu, Dacai; Zhao, Chong; Wang, Xuejun; Liu, Jinbao.

In: Cellular Physiology and Biochemistry, Vol. 49, No. 2, 01.09.2018, p. 780-797.

Research output: Contribution to journalArticle

Chen, X, Yang, Q, Chen, J, Zhang, P, Huang, Q, Zhang, X, Yang, L, Xu, D, Zhao, C, Wang, X & Liu, J 2018, 'Inhibition of Proteasomal Deubiquitinase by Silver Complex Induces Apoptosis in Non-Small Cell Lung Cancer Cells', Cellular Physiology and Biochemistry, vol. 49, no. 2, pp. 780-797. https://doi.org/10.1159/000493041
Chen, Xin ; Yang, Qianqian ; Chen, Jinghong ; Zhang, Peiquan ; Huang, Qingtian ; Zhang, Xiaolan ; Yang, Li ; Xu, Dacai ; Zhao, Chong ; Wang, Xuejun ; Liu, Jinbao. / Inhibition of Proteasomal Deubiquitinase by Silver Complex Induces Apoptosis in Non-Small Cell Lung Cancer Cells. In: Cellular Physiology and Biochemistry. 2018 ; Vol. 49, No. 2. pp. 780-797.
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AU - Huang, Qingtian

AU - Zhang, Xiaolan

AU - Yang, Li

AU - Xu, Dacai

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