Cadmium pyrithione suppresses tumor growth in vitro and in vivo through inhibition of proteasomal deubiquitinase

Xin Chen, Jinjie Wu, Qianqian Yang, Xiaolan Zhang, Peiquan Zhang, Siyan Liao, Zhimin He, Xuejun Wang, Chong Zhao, Jinbao Liu

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The ubiquitin–proteasome system (UPS) is indispensable to the protein quality control in eukaryotic cells. Due to the remarkable clinical success of using proteasome inhibitors for clinical treatment of multiple myeloma, it is anticipated that targeting the UPS upstream of the proteasome step be an effective strategy for cancer therapy. Deubiquitinases (DUB) are proteases that remove ubiquitin from target proteins and therefore regulate multiple cellular processes including some signaling pathways altered in cancer cells. Thus, targeting DUB is a promising strategy for cancer drug discovery. Previously, we have reported that metal complexes, such as copper and gold complexes, can disrupt the UPS via suppressing the activity of 19S proteasome-associated DUBs and/or of the 20S proteasomes, thereby inducing cancer cell death. In this study, we found that cadmium pyrithione (CdPT) treatment led to remarkable accumulation of ubiquitinated proteins in cultured cancer cells and primary leukemia cells. CdPT potently inhibited the activity of proteasomal DUBs (USP14 and UCHL5), but slightly inhibited 20S proteasome activity. The anti-cancer activity of CdPT was associated with triggering apoptosis via caspase activation. Moreover, treatment with CdPT inhibited proteasome function and repressed tumor growth in animal xenograft models. Our results show that cadmium-containing complex CdPT may function as a novel proteasomal DUB inhibitor and suggest appealing prospects for cancer treatment.

Original languageEnglish (US)
Pages (from-to)29-43
Number of pages15
JournalBioMetals
Volume31
Issue number1
DOIs
StatePublished - Feb 1 2018

Fingerprint

proteasome endopeptidase complex
Cadmium
Proteasome Endopeptidase Complex
Tumors
cadmium
neoplasms
Growth
Neoplasms
Cell death
Proteins
Cells
Ubiquitinated Proteins
myeloma
Proteasome Inhibitors
Oncology
proteins
caspases
Coordination Complexes
ubiquitin
Caspases

Keywords

  • Cadmium
  • Deubiquitinase
  • Proteasome
  • Pyrithione
  • Tumor

ASJC Scopus subject areas

  • Biomaterials
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Metals and Alloys

Cite this

Cadmium pyrithione suppresses tumor growth in vitro and in vivo through inhibition of proteasomal deubiquitinase. / Chen, Xin; Wu, Jinjie; Yang, Qianqian; Zhang, Xiaolan; Zhang, Peiquan; Liao, Siyan; He, Zhimin; Wang, Xuejun; Zhao, Chong; Liu, Jinbao.

In: BioMetals, Vol. 31, No. 1, 01.02.2018, p. 29-43.

Research output: Contribution to journalArticle

Chen, X, Wu, J, Yang, Q, Zhang, X, Zhang, P, Liao, S, He, Z, Wang, X, Zhao, C & Liu, J 2018, 'Cadmium pyrithione suppresses tumor growth in vitro and in vivo through inhibition of proteasomal deubiquitinase', BioMetals, vol. 31, no. 1, pp. 29-43. https://doi.org/10.1007/s10534-017-0062-6
Chen, Xin ; Wu, Jinjie ; Yang, Qianqian ; Zhang, Xiaolan ; Zhang, Peiquan ; Liao, Siyan ; He, Zhimin ; Wang, Xuejun ; Zhao, Chong ; Liu, Jinbao. / Cadmium pyrithione suppresses tumor growth in vitro and in vivo through inhibition of proteasomal deubiquitinase. In: BioMetals. 2018 ; Vol. 31, No. 1. pp. 29-43.
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