Activation of Erk and p53 regulates copper oxide nanoparticle-induced cytotoxicity in keratinocytes and fibroblasts

Abstract

Copper oxide nanoparticles (CuONP) have attracted increasing attention due to their unique properties and have been extensively utilized in industrial and commercial applications. For example, their antimicrobial capability endows CuONP with applications in dressings and textiles against bacterial infections. Along with the wide applications, concerns about the possible effects of CuONP on humans are also increasing. It is crucial to evaluate the safety and impact of CuONP on humans, and especially the skin, prior to their practical application. The potential toxicity of CuONP to skin keratinocytes has been reported recently. However, the underlying mechanism of toxicity in skin cells has remained unclear. In the present work, we explored the possible mechanism of the cytotoxicity of CuONP in HaCaT human keratinocytes and mouse embryonic fibroblasts (MEF). CuONP exposure induced viability loss, migration inhibition, and G 2 /M phase cycle arrest in both cell types. CuONP significantly induced mitogen-activated protein kinase (extracellular signal-regulated kinase [Erk], p38, and c-Jun N-terminal kinase [JNK]) activation in dose- and time-dependent manners. U0126 (an inhibitor of Erk), but not SB 239063 (an inhibitor of p38) or SP600125 (an inhibitor of JNK), enhanced CuONP-induced viability loss. CuONP also induced decreases in p53 and p-p53 levels in both cell types. Cyclic pifithrin-α, an inhibitor of p53 transcriptional activity, enhanced CuONP-induced viability loss. Nutlin-3α, a p53 stabilizer, prevented CuONP-induced viability loss in HaCaT cells, but not in MEF cells, due to the inherent toxicity of nutlin-3α to MEF. Moreover, the experiments on primary keratinocytes are in accordance with the conclusions acquired from HaCaT and MEF cells. These data demonstrate that the activation of Erk and p53 plays an important role in CuONP-induced cytotoxicity, and agents that preserve Erk or p53 activation may prevent CuONP-induced cytotoxicity.

Cytotoxicity of various types of gold-mesoporous silica nanoparticles in human breast cancer cells

“…42 In contrast, ERK is generally associated with proliferation and growth. 43 Here, we showed that treatment with each of the AuNPs resulted in a marked activation of JNK and the inactivation of ERK; however, only bare AuNPs significantly increased the phosphorylation of p38. Differences in the curvature of the different types of AuNPs and the release of CTAB in the cell, thereby inducing the activation of p38 might explain this phenomenon.…”

Gene Expression and Epigenetic Changes in Mice Following Inhalation of Copper(II) Oxide Nanoparticles

“…A six-week exposure period impacted on cell cycle-related processes. Although no similar results in mice have been reported, it has been shown that CuO NP may cause a cell cycle arrest in human keratinocytes, mouse embryonic fibroblasts [21], and in human umbilical vein endothelial cells (HUVECs) [22]. In a model of poorly differentiated hepatocellular carcinoma cells, the cell cycle arrest was possibly caused by histone H2AX phosphorylation, resulting from DNA damage [17].…”

Can CuO nanoparticles lead to epigenetic regulation of antioxidant enzyme system?

“…The well-known mechanism for activation of apoptosis by CuO NPs is a mitochondrial-mediated pathway which is initiated by ROS generation. It results in the destruction of the mitochondrial membrane via ROS (Liu et al, 2016), which , in turn,leads to the activation of p53 and correspondingly leads to an increase in the Bax/Bcl2 ratio (Luo et al, 2014). It is likely that activation of apoptosis by mitochondrial membrane damage results in a cascade which leads to the activation of caspase 3 (Ahmad et al, 2016).…”