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Published on: June 21, 2015
Impairment of antioxidant defenses as a contributor to arsenite-induced cell transformation
Jing Wu1, Anna Sowinska, Xi Huang
1Department of Environmental Medicine, New York University School of Medicine, New York, NY 10016, USA. wuj04@nyumc.org
Abstract:
Arsenite (As) causes transformation of human osteogenic sarcoma cells (HOS) when applied continuously at low doses (0.1-0.5 μM) during 8-weeks of exposure. However, the mechanisms by which As transforms human cells are not known. We investigated whether alterations occurred in gene expression and protein levels of antioxidant defense proteins, such as superoxide dismutase 1 (SOD1) and ferritin. In comparison to control HOS cells, 0.1 μM As induced greater cell proliferation and decreased anti-oxidant defenses. The tumor suppressor protein p53 was also decreased at both mRNA and protein levels. Further, pig3 (p53-induced-gene 3), a homolog of NQO1 (NADPH quinone oxidoreductase 1), was also down-regulated after 8 weeks of As challenge. The treatment of HOS cells with dicumarol, a NQO1 inhibitor, caused a dose-dependent decline in p53 protein levels, proving the effect of an antioxidant enzyme on p53 expression and, potentially, down-stream processes. Caffeic acid phenethyl ester, an antioxidant, prevented the As-induced decreases in SOD1, p53, and ferritin mRNA and protein levels. SOD1, p53 and ferritin levels were inversely related to As-induced cell proliferation. Cumulatively, these results strongly suggest that impairment in antioxidant defenses contributes to As-induced human cell transformation and that the p53 pathway is involved in the process.
Insights
Low-dose arsenite exposure transforms human cells by impairing antioxidant defenses, decreasing superoxide dismutase 1 (SOD1) and p53 levels. Antioxidant treatment protected against arsenite-induced cell transformation.
Area of Science:
- Toxicology
- Cell Biology
- Biochemistry
Background:
- Arsenite (As) is a known carcinogen that can transform human cells.
- The mechanisms underlying arsenite-induced cell transformation remain largely unknown.
- Antioxidant defense systems play a crucial role in cellular protection against toxic insults.
Purpose of the Study:
- To investigate the role of antioxidant defense proteins in arsenite-induced human cell transformation.
- To examine the impact of arsenite on gene expression and protein levels of key antioxidant enzymes.
- To elucidate the involvement of the p53 pathway in arsenite-induced cellular changes.
Main Methods:
- Human osteogenic sarcoma cells (HOS) were exposed to low-dose arsenite (0.1-0.5 μM) for 8 weeks.
- Gene expression and protein levels of superoxide dismutase 1 (SOD1), ferritin, p53, and pig3 were analyzed.
- The effects of NQO1 inhibition (dicumarol) and antioxidant treatment (caffeic acid phenethyl ester) were evaluated.
Main Results:
- Arsenite exposure led to increased cell proliferation and decreased antioxidant defenses (SOD1, ferritin).
- Both mRNA and protein levels of the tumor suppressor p53 were significantly reduced.
- NQO1 inhibition decreased p53 levels, while antioxidant treatment prevented arsenite-induced reductions in SOD1, p53, and ferritin.
Conclusions:
- Impairment of antioxidant defenses contributes to arsenite-induced human cell transformation.
- The p53 pathway is implicated in the cellular response to arsenite exposure.
- Maintaining antioxidant balance is critical for preventing arsenite-mediated cellular transformation.
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