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Article

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

by 1,†, 1,†, 2,3,4, 5,* and 1,*
1
Department of Biochemistry, National Defense Medical Center, Taipei 114, Taiwan
2
Department of Urology, Mackay Memorial Hospital, Taipei 104, Taiwan
3
Department of Medicine, Mackay Medical College, New Taipei 252, Taiwan
4
Department of Cosmetic Applications and Management, Mackay Junior College of Medicine, Nursing, and Management, Taipei 112, Taiwan
5
Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(20), 5225; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20205225
Received: 29 August 2019 / Revised: 17 October 2019 / Accepted: 19 October 2019 / Published: 22 October 2019
(This article belongs to the Special Issue Crosstalk between Circadian Rhythm and Diseases)
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. View Full-Text
Keywords: copper sulfate; cytotoxicity; reactive oxygen species; disulfiram; differentiated embryonic chondrocyte gene 1 copper sulfate; cytotoxicity; reactive oxygen species; disulfiram; differentiated embryonic chondrocyte gene 1
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MDPI and ACS Style

Chen, S.-Y.; Liu, S.-T.; Lin, W.-R.; Lin, C.-K.; Huang, S.-M. The Mechanisms Underlying the Cytotoxic Effects of Copper Via Differentiated Embryonic Chondrocyte Gene 1. Int. J. Mol. Sci. 2019, 20, 5225. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20205225

AMA Style

Chen S-Y, Liu S-T, Lin W-R, Lin C-K, Huang S-M. The Mechanisms Underlying the Cytotoxic Effects of Copper Via Differentiated Embryonic Chondrocyte Gene 1. International Journal of Molecular Sciences. 2019; 20(20):5225. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20205225

Chicago/Turabian Style

Chen, Ssu-Yu, Shu-Ting Liu, Wun-Rong Lin, Chi-Kang Lin, and Shih-Ming Huang. 2019. "The Mechanisms Underlying the Cytotoxic Effects of Copper Via Differentiated Embryonic Chondrocyte Gene 1" International Journal of Molecular Sciences 20, no. 20: 5225. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20205225

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