2024-03-28T11:38:18Z
https://tsukuba.repo.nii.ac.jp/oai
oai:tsukuba.repo.nii.ac.jp:00038146
2022-04-27T09:07:49Z
2780:5125
2780:551
3:62:5592:5124
Copper diethyldithiocarbamate as an activator of Nrf2 in cultured vascular endothelial cells
新開, 泰弘
熊谷, 嘉人
Fujie, Tomoya
Murakami, Masaki
Yoshida, Eiko
Tachinami, Tadashi
Shinkai, Yasuhiro
Fujiwara, Yasuyuki
Yamamoto, Chika
Kumagai, Yoshito
Naka, Hiroshi
Kaji, Toshiyuki
The interest in organic–inorganic hybrid molecules as molecular probes for biological systems has been growing rapidly. Such hybrid molecules exhibit unique biological activities. Herein, copper(II) bis(diethyldithiocarbamate) (Cu10) was found to activate the transcription factor NF-E2-related factor 2 (Nrf2), which is responsible for regulating antioxidant and phase II xenobiotic enzymes, in vascular endothelial cells. The copper complex rapidly accumulated within cells and induced nuclear translocation of Nrf2, leading to upregulation of the expression of downstream proteins without cytotoxic effects. However, while copper bis(2-hydroxyethyl)dithiocarbamate activated Nrf2, copper ion, diethyldithiocarbamate ligand with or without zinc or iron failed to exhibit this activity. Intracellular accumulation of Cu10 was higher than that of Cu(II) and Cu(I). While the accumulation of copper(II) bis(dimethyldithiocarbamate) was reduced by small interfering RNA (siRNA)-mediated knockdown of the copper transporter CTR1, the knockdown did not affect Cu10 accumulation, indicating that Cu10 rapidly enters vascular endothelial cells via CTR1-independent mechanisms. In addition, copper and iron complexes with other ligands tested could not activate Nrf2, suggesting that the intramolecular interaction between copper and dithiocarbamate ligand is important for the activation of the transcription factor. Cu10 induced the expression of heme oxygenase-1, NAD(P)H quinone oxidoreductase 1, and γ-glutamylcysteine synthetase, downstream proteins of Nrf2. It was suggested that Cu10-induced activation of Nrf2 was due to proteasome inhibition as well as binding to Kelch-like ECH-associated protein 1. Since the effects of Cu10 on vascular endothelial cells are unique and diverse, the copper complex may be a good molecular probe to analyze the functions of the cells.
journal article
Springer Berlin Heidelberg
2016-04
application/pdf
Journal of biological inorganic chemistry : JBIC
2
21
263
273
0949-8257
AA11133001
https://tsukuba.repo.nii.ac.jp/record/38146/files/JBIC_21-2.pdf
eng
26825804
10.1007/s00775-016-1337-z
© The Author(s) 2016. This article is published with open access at Springerlink.com
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.