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

Abstract

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.

Differential Cytotoxicity Mechanisms of Copper Complexed with Disulfiram in Oral Cancer Cells

“…We previously reported that ROS production may result in stabilization of HIF-1α [ 31 ]. To determine whether that occurs in OECM-1 or SG cells, we assessed the effects of the ROS scavenger NAC ( Figure 10 ).…”

Molecular Mechanisms Underlying Protective Role of Quercetin on Copper Sulfate-Induced Nephrotoxicity in Mice

“…Under normal conditions, the Nrf2 activity is suppressed, as it is sequestered in the cytoplasm by binding to Kelch-like ECH-associated protein 1 (Keap1) ( 50 ). It has been reported that CuSO 4 exposure can induce the expression of Nrf2 and downstream gene HO-1 in Hela, HEC-1A, HEK293, and A549 cells ( 16 ). In the present study, CuSO 4 significantly increased the expression of Nrf2 and HO-1 expression in the kidney tissues ( Figures 7E,F ).…”

“…Earlier studies also reported that the molecular mechanism of Cu nephrotoxicity involved oxidative stress, apoptosis and autophagy, which were characterized by various signaling pathways, including mammalian target of rapamycin (mTOR) pathway, nuclear factor kappa B (NF-κB) pathway, p53 pathway, and the endoplasmic reticulum (ER) stress pathway ( 13 – 15 ). In in vitro models, CuSO 4 -induced cell death is associated with increases in the levels of senescence, apoptosis, autophagy, mitochondrial damage, and excessive production of reactive oxygen species (ROS) ( 16 ). Recently, Alharbi and colleagues found that turmeric could protect CuSO 4 -induced nephrotoxicity in rats by inhibiting oxidative stress and apoptosis ( 14 ).…”

Impact of Differentiated Macrophage-Like Cells on the Transcriptional Toxicity Profile of CuO Nanoparticles in Co-Cultured Lung Epithelial Cells

“…The repression of DNA repair pathways despite the induction of DNA damage is still not fully understood; however, Collin and colleagues suggested that cellular senescence may result in repressed DNA repair genes [ 39 ]. An induction of senescence was, so far, shown for copper sulfate in HeLa cells and for Cu NP in Enchytraeus crypticus [ 40 , 41 ]; a potential induction of senescence by CuO NP in mammalian cells remains to be elucidated.…”