Cargando…

The Mechanisms Underlying the Cytotoxic Effects of Copper Via Differentiated Embryonic Chondrocyte Gene 1

Copper is an essential trace element within cells, but it also exerts cytotoxic effects through induction of reactive oxygen species (ROS) production. To determine the mechanisms underlying copper-induced ROS production, we examined the effects of copper sulfate in HeLa cells. Exposure to copper sul...

Descripción completa

Detalles Bibliográficos
Autores principales: Chen, Ssu-Yu, Liu, Shu-Ting, Lin, Wun-Rong, Lin, Chi-Kang, Huang, Shih-Ming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834119/
https://www.ncbi.nlm.nih.gov/pubmed/31652494
http://dx.doi.org/10.3390/ijms20205225
_version_ 1783466421917843456
author Chen, Ssu-Yu
Liu, Shu-Ting
Lin, Wun-Rong
Lin, Chi-Kang
Huang, Shih-Ming
author_facet Chen, Ssu-Yu
Liu, Shu-Ting
Lin, Wun-Rong
Lin, Chi-Kang
Huang, Shih-Ming
author_sort Chen, Ssu-Yu
collection PubMed
description Copper is an essential trace element within cells, but it also exerts cytotoxic effects through induction of reactive oxygen species (ROS) production. To determine the mechanisms underlying copper-induced ROS production, we examined the effects of copper sulfate in HeLa cells. Exposure to copper sulfate led to dose-dependent decreases in HeLa cell viability, along with increases in the subG1 and G2/M populations and corresponding decreases in the G1 population. Copper sulfate also increased the levels of apoptosis, senescence, mitochondrial dysfunction, autophagy, ROS, and the expression of several stress proteins, including ATF3, c-Fos, DEC1 (differentiated embryonic chondrocyte gene 1), p21, p53, and HIF-1α (hypoxia-inducible factor 1 alpha). The suppression of copper-induced ROS generation by the ROS scavenger N-acetyl cysteine verified copper’s functional role, while the suppression of copper’s effects by the copper chelator disulfiram, confirmed its specificity. Selective induction of HIF-1α, p53, and phosphorylated ERK proteins by copper was blocked by the knockdown of the transcription factor DEC1, suggesting copper’s effects are mediated by DEC1. In addition to HeLa cells, copper also exerted cytotoxic effects in human endometrial (HEC-1-A) and lung (A549) adenocarcinoma cells, but not in normal human kidney (HEK293) or bronchial (Beas-2B) epithelial cells. These findings shed new light on the functional roles of copper within cells.
format Online
Article
Text
id pubmed-6834119
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-68341192019-11-25 The Mechanisms Underlying the Cytotoxic Effects of Copper Via Differentiated Embryonic Chondrocyte Gene 1 Chen, Ssu-Yu Liu, Shu-Ting Lin, Wun-Rong Lin, Chi-Kang Huang, Shih-Ming Int J Mol Sci Article Copper is an essential trace element within cells, but it also exerts cytotoxic effects through induction of reactive oxygen species (ROS) production. To determine the mechanisms underlying copper-induced ROS production, we examined the effects of copper sulfate in HeLa cells. Exposure to copper sulfate led to dose-dependent decreases in HeLa cell viability, along with increases in the subG1 and G2/M populations and corresponding decreases in the G1 population. Copper sulfate also increased the levels of apoptosis, senescence, mitochondrial dysfunction, autophagy, ROS, and the expression of several stress proteins, including ATF3, c-Fos, DEC1 (differentiated embryonic chondrocyte gene 1), p21, p53, and HIF-1α (hypoxia-inducible factor 1 alpha). The suppression of copper-induced ROS generation by the ROS scavenger N-acetyl cysteine verified copper’s functional role, while the suppression of copper’s effects by the copper chelator disulfiram, confirmed its specificity. Selective induction of HIF-1α, p53, and phosphorylated ERK proteins by copper was blocked by the knockdown of the transcription factor DEC1, suggesting copper’s effects are mediated by DEC1. In addition to HeLa cells, copper also exerted cytotoxic effects in human endometrial (HEC-1-A) and lung (A549) adenocarcinoma cells, but not in normal human kidney (HEK293) or bronchial (Beas-2B) epithelial cells. These findings shed new light on the functional roles of copper within cells. MDPI 2019-10-22 /pmc/articles/PMC6834119/ /pubmed/31652494 http://dx.doi.org/10.3390/ijms20205225 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chen, Ssu-Yu
Liu, Shu-Ting
Lin, Wun-Rong
Lin, Chi-Kang
Huang, Shih-Ming
The Mechanisms Underlying the Cytotoxic Effects of Copper Via Differentiated Embryonic Chondrocyte Gene 1
title The Mechanisms Underlying the Cytotoxic Effects of Copper Via Differentiated Embryonic Chondrocyte Gene 1
title_full The Mechanisms Underlying the Cytotoxic Effects of Copper Via Differentiated Embryonic Chondrocyte Gene 1
title_fullStr The Mechanisms Underlying the Cytotoxic Effects of Copper Via Differentiated Embryonic Chondrocyte Gene 1
title_full_unstemmed The Mechanisms Underlying the Cytotoxic Effects of Copper Via Differentiated Embryonic Chondrocyte Gene 1
title_short The Mechanisms Underlying the Cytotoxic Effects of Copper Via Differentiated Embryonic Chondrocyte Gene 1
title_sort mechanisms underlying the cytotoxic effects of copper via differentiated embryonic chondrocyte gene 1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834119/
https://www.ncbi.nlm.nih.gov/pubmed/31652494
http://dx.doi.org/10.3390/ijms20205225
work_keys_str_mv AT chenssuyu themechanismsunderlyingthecytotoxiceffectsofcopperviadifferentiatedembryonicchondrocytegene1
AT liushuting themechanismsunderlyingthecytotoxiceffectsofcopperviadifferentiatedembryonicchondrocytegene1
AT linwunrong themechanismsunderlyingthecytotoxiceffectsofcopperviadifferentiatedembryonicchondrocytegene1
AT linchikang themechanismsunderlyingthecytotoxiceffectsofcopperviadifferentiatedembryonicchondrocytegene1
AT huangshihming themechanismsunderlyingthecytotoxiceffectsofcopperviadifferentiatedembryonicchondrocytegene1
AT chenssuyu mechanismsunderlyingthecytotoxiceffectsofcopperviadifferentiatedembryonicchondrocytegene1
AT liushuting mechanismsunderlyingthecytotoxiceffectsofcopperviadifferentiatedembryonicchondrocytegene1
AT linwunrong mechanismsunderlyingthecytotoxiceffectsofcopperviadifferentiatedembryonicchondrocytegene1
AT linchikang mechanismsunderlyingthecytotoxiceffectsofcopperviadifferentiatedembryonicchondrocytegene1
AT huangshihming mechanismsunderlyingthecytotoxiceffectsofcopperviadifferentiatedembryonicchondrocytegene1