Dose-dependent genotoxicity of copper oxide nanoparticles stimulated by reactive oxygen species in human lung epithelial cells

Background: Growing evidence indicates that heme oxygenase-1 (HO-1) is up-regulated in malignancies and subsequently alters tumor aggressiveness and various cancer-related factors, such as high glucose (HG) levels. HO-1 expression can be induced when glucose concentrations are above 25 mM; however, the role of HO-1 in lung cancer patients with diabetes remains unknown. Therefore, in this study we investigated the promotion of tumor cell invasion and the expression of metastasis-associated proteins by inducing the up-regulation of HO-1 expression by HG treatment in A549 human lung epithelial cells. Methods: The expression of HO-1and metastasis-associated protein expression was explored by western blot analysis. HO-1 enzymatic activity, reactive oxygen species (ROS) production and TGF-β1 production were examined by ELISA. Invasiveness was analyzed using a Transwell chamber. Results: HG treatment of A549 cells induced an increase in HO-1 expression, which was mediated by the HG-induced generation of reactive oxygen species (ROS) and transforming growth factor-β1 (TGF-β1) in a concentration- and time-dependent manner. Following the increase in HO-1 expression, the enzymatic activity of HO-1 also increased in HG-treated cells. Pretreatment with N-acetyl-L-cysteine (NAC) or with phosphatidylinositol 3-kinase (PI3K)/Akt inhibitors attenuated the HG-induced increase in HO-1 expression. HG treatment of A549 cells enhanced the invasion potential of these cells, as shown with a Transwell assay, and increased metastasis-associated protein expression. However, HO-1 siRNA transfection significantly decreased these capabilities. Conclusion: this study is the first to demonstrate that HG treatment of A549 human lung epithelial cells promotes tumor cell invasion and increases metastasis-associated protein expression by up-regulating HO-1 expression via ROS or the TGF-β1/PI3K/Akt signaling pathway.

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Copper Oxide Nanoparticles Cause a Dose-Dependent Toxicity via Inducing Reactive Oxygen Species in Drosophila

Nanomaterials ◽

10.3390/nano8100824 ◽

2018 ◽

Vol 8 (10) ◽

pp. 824 ◽

Cited By ~ 14

Author(s):

Eugene Baeg ◽

Kanidta Sooklert ◽

Amornpun Sereemaspun

Keyword(s):

Reactive Oxygen Species ◽

Copper Oxide ◽

Reactive Oxygen ◽

Copper Oxide Nanoparticles ◽

The Body ◽

Model Systems ◽

In Vivo Model ◽

Oxide Nanoparticles ◽

Oxygen Species ◽

Dose Dependent

Copper oxide nanoparticles (CuONPs) have attracted considerable attention, because of their biocide potential and capability for optical imaging, however CuONPs were shown to be highly toxic in various experimental model systems. In this study, mechanism underlying CuONP-induced toxicity was investigated using Drosophila as an in vivo model. Upon oral route of administration, CuONPs accumulated in the body, and caused a dose-dependent decrease in egg-to-adult survivorship and a delay in development. In particular, transmission electron microscopy analysis revealed CuONPs were detected inside the intestinal epithelial cells and lumen. A drastic increase in apoptosis and reactive oxygen species was also observed in the gut exposed to CuONPs. Importantly, we found that inhibition of the transcription factor Nrf2 further enhances the toxicity caused by CuONPs. These observations suggest that CuONPs disrupt the gut homeostasis and that oxidative stress serves as one of the primary causes of CuONP-induced toxicity in Drosophila.

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