Hinokitiol copper complex inhibits proteasomal deubiquitination and induces paraptosis-like cell death in human cancer cells

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

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The ubiquitin-proteasome system (UPS) plays a central role in the regulation of proteins that control cell growth and apoptosis and has therefore become an important target for anticancer therapy. Several constitutive subunits of the 19S proteasome display deubiquitinase (DUB) activity, suggesting that ubiquitin modification of proteins is dynamically regulated. Our study and others have shown that metal complexes, such as copper complexes, can induce cancer cell apoptosis through inhibiting 19S proteasome-associated DUBs and/or 20S proteasome activity. In this study, we found that (1) Hinokitiol copper complex (HK-Cu) induces striking accumulation of ubiquitinated proteins in A549 and K562 cells (2) HK-Cu potently inhibits the activity of the 19S proteasomal DUBs much more effectively than it does to the chymotrypsin-like activity of the 20S proteasome (3) HK-Cu effectively induces caspase-independent and paraptosis-like cell death in A549 and K562 cells, and (4) HK-Cu-induced cell death depends on ATF4-assosiated ER stress but is apparently not related to ROS generation. Altogether, these data indicate that HK-Cu can inhibit the activity of the 19S proteasomal DUBs and induce paraptosis-like cell death, representing a new drug candidate for cancer treatment.

Original languageEnglish (US)
JournalEuropean Journal of Pharmacology
DOIs
StateAccepted/In press - 2017
Externally publishedYes

Fingerprint

Proteasome Endopeptidase Complex
Copper
Cell Death
K562 Cells
Neoplasms
Ubiquitin
Ubiquitinated Proteins
Apoptosis
Coordination Complexes
Chymotrypsin
Caspases
Proteins
beta-thujaplicin
Growth
Pharmaceutical Preparations
A549 Cells

Keywords

  • Cancer
  • Copper
  • Deubiquitinase
  • Hinokitiol
  • Paraptosis
  • Proteasome

ASJC Scopus subject areas

  • Pharmacology

Cite this

Hinokitiol copper complex inhibits proteasomal deubiquitination and induces paraptosis-like cell death in human cancer cells. / Chen, Xin; Zhang, Xiaolan; Chen, Jinghong; Yang, Qianqian; Yang, Li; Xu, Dacai; Zhang, Peiquan; Wang, Xuejun; Liu, Jinbao.

In: European Journal of Pharmacology, 2017.

Research output: Contribution to journalArticle

Chen, Xin ; Zhang, Xiaolan ; Chen, Jinghong ; Yang, Qianqian ; Yang, Li ; Xu, Dacai ; Zhang, Peiquan ; Wang, Xuejun ; Liu, Jinbao. / Hinokitiol copper complex inhibits proteasomal deubiquitination and induces paraptosis-like cell death in human cancer cells. In: European Journal of Pharmacology. 2017.
@article{5f68f6a0e9ae4540bf86f660f56a9307,
title = "Hinokitiol copper complex inhibits proteasomal deubiquitination and induces paraptosis-like cell death in human cancer cells",
abstract = "The ubiquitin-proteasome system (UPS) plays a central role in the regulation of proteins that control cell growth and apoptosis and has therefore become an important target for anticancer therapy. Several constitutive subunits of the 19S proteasome display deubiquitinase (DUB) activity, suggesting that ubiquitin modification of proteins is dynamically regulated. Our study and others have shown that metal complexes, such as copper complexes, can induce cancer cell apoptosis through inhibiting 19S proteasome-associated DUBs and/or 20S proteasome activity. In this study, we found that (1) Hinokitiol copper complex (HK-Cu) induces striking accumulation of ubiquitinated proteins in A549 and K562 cells (2) HK-Cu potently inhibits the activity of the 19S proteasomal DUBs much more effectively than it does to the chymotrypsin-like activity of the 20S proteasome (3) HK-Cu effectively induces caspase-independent and paraptosis-like cell death in A549 and K562 cells, and (4) HK-Cu-induced cell death depends on ATF4-assosiated ER stress but is apparently not related to ROS generation. Altogether, these data indicate that HK-Cu can inhibit the activity of the 19S proteasomal DUBs and induce paraptosis-like cell death, representing a new drug candidate for cancer treatment.",
keywords = "Cancer, Copper, Deubiquitinase, Hinokitiol, Paraptosis, Proteasome",
author = "Xin Chen and Xiaolan Zhang and Jinghong Chen and Qianqian Yang and Li Yang and Dacai Xu and Peiquan Zhang and Xuejun Wang and Jinbao Liu",
year = "2017",
doi = "10.1016/j.ejphar.2017.09.003",
language = "English (US)",
journal = "European Journal of Pharmacology",
issn = "0014-2999",
publisher = "Elsevier",

}

TY - JOUR

T1 - Hinokitiol copper complex inhibits proteasomal deubiquitination and induces paraptosis-like cell death in human cancer cells

AU - Chen, Xin

AU - Zhang, Xiaolan

AU - Chen, Jinghong

AU - Yang, Qianqian

AU - Yang, Li

AU - Xu, Dacai

AU - Zhang, Peiquan

AU - Wang, Xuejun

AU - Liu, Jinbao

PY - 2017

Y1 - 2017

N2 - The ubiquitin-proteasome system (UPS) plays a central role in the regulation of proteins that control cell growth and apoptosis and has therefore become an important target for anticancer therapy. Several constitutive subunits of the 19S proteasome display deubiquitinase (DUB) activity, suggesting that ubiquitin modification of proteins is dynamically regulated. Our study and others have shown that metal complexes, such as copper complexes, can induce cancer cell apoptosis through inhibiting 19S proteasome-associated DUBs and/or 20S proteasome activity. In this study, we found that (1) Hinokitiol copper complex (HK-Cu) induces striking accumulation of ubiquitinated proteins in A549 and K562 cells (2) HK-Cu potently inhibits the activity of the 19S proteasomal DUBs much more effectively than it does to the chymotrypsin-like activity of the 20S proteasome (3) HK-Cu effectively induces caspase-independent and paraptosis-like cell death in A549 and K562 cells, and (4) HK-Cu-induced cell death depends on ATF4-assosiated ER stress but is apparently not related to ROS generation. Altogether, these data indicate that HK-Cu can inhibit the activity of the 19S proteasomal DUBs and induce paraptosis-like cell death, representing a new drug candidate for cancer treatment.

AB - The ubiquitin-proteasome system (UPS) plays a central role in the regulation of proteins that control cell growth and apoptosis and has therefore become an important target for anticancer therapy. Several constitutive subunits of the 19S proteasome display deubiquitinase (DUB) activity, suggesting that ubiquitin modification of proteins is dynamically regulated. Our study and others have shown that metal complexes, such as copper complexes, can induce cancer cell apoptosis through inhibiting 19S proteasome-associated DUBs and/or 20S proteasome activity. In this study, we found that (1) Hinokitiol copper complex (HK-Cu) induces striking accumulation of ubiquitinated proteins in A549 and K562 cells (2) HK-Cu potently inhibits the activity of the 19S proteasomal DUBs much more effectively than it does to the chymotrypsin-like activity of the 20S proteasome (3) HK-Cu effectively induces caspase-independent and paraptosis-like cell death in A549 and K562 cells, and (4) HK-Cu-induced cell death depends on ATF4-assosiated ER stress but is apparently not related to ROS generation. Altogether, these data indicate that HK-Cu can inhibit the activity of the 19S proteasomal DUBs and induce paraptosis-like cell death, representing a new drug candidate for cancer treatment.

KW - Cancer

KW - Copper

KW - Deubiquitinase

KW - Hinokitiol

KW - Paraptosis

KW - Proteasome

UR - http://www.scopus.com/inward/record.url?scp=85029495755&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029495755&partnerID=8YFLogxK

U2 - 10.1016/j.ejphar.2017.09.003

DO - 10.1016/j.ejphar.2017.09.003

M3 - Article

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

ER -