Neoplastic Transformation of Human Small Airway Epithelial Cells Induced by Arsenic

Abstract

Human small airway epithelial cells (SAECs) previously immortalized with human telomerase reverse transcriptase (h-TERT) were continuously treated with sodium arsenite at a dose of 0.5 μg/mL in culture for up to 6 months. Arsenic-treated cells progressively displayed an increase in transformed phenotype including enhanced growth saturation density, plating efficiency, and anchorage-independent growth and invasion capability compared with their nontreated control cells. To determine whether arsenicinduced cell transformation was associated with genomic instability, treated and control cells were also analyzed for micronuclei formation. A 4.8-fold increase in micronuclei incidence in arsenic-treated cells was detected in conjunction with increased N-phosphonacetyl-L-aspartate (PALA)-resistant characteristics. In addition, arsenic-treated cells showed an increase in c-H-ras, c-myc, and c-fos protein expression relative to controls. The change in oncoprotein expression correlated with a decrease in wildtype p53 expression and hyperphosphorylated retinoblastoma. Taken together, these results strongly suggest that h-TERT immortalized human small airway epithelial cells underwent step-wise transformation after inorganic arsenic treatment.

Continuous activation of Nrf2 and its target antioxidant enzymes leads to arsenite-induced malignant transformation of human bronchial epithelial cells

“…In in vitro studies, neoplastic transformation caused by long-term exposure to low concentrations of inorganic arsenic was established in various cell lines (Achanzar et al, 2002;Sens et al, 2004;Wen et al, 2007;Li et al, 2010;Chain et al, 2004;Pi et al, 2008). For HBE cell line, Xu et al (2012) reported that HBE cells could be transformed by long-term (30 passages) exposure to 1.0 μM NaAsO 2 , as determined by anchorage-independent growth in soft agar and tumorigenesis in nude mice.…”

Blockade of p53 by HIF-2α, but not HIF-1α, is involved in arsenite-induced malignant transformation of human bronchial epithelial cells

“…Chronic exposure to arsenite causes carcinogenesis of lung, skin, and bladder (Shen et al 2008;Wen et al 2008). Long-term exposure to arsenite results in neoplastic transformation of human keratinocytes and small airway epithelial cells (Pi et al 2002;Wen et al 2008). The neoplastic transformation induced by low levels of arsenite is associated with cell proliferation (Wen et al 2008).…”

“…Long-term exposure to arsenite results in neoplastic transformation of human keratinocytes and small airway epithelial cells (Pi et al 2002;Wen et al 2008). The neoplastic transformation induced by low levels of arsenite is associated with cell proliferation (Wen et al 2008). In the present study, 0.5, 1.0, and 2.0 M concentrations of arsenite did not cause cell death and were lower than levels in drinking water in areas where arsenicosis is common (Pi et al 2002).…”

“…Inorganic arsenic is a potent human carcinogen that causes cancers of the lung, skin, kidney, urinary bladder, and liver (Shen et al 2008;Wen et al 2008). Lung is considered to be the most sensitive site for arsenic toxicity (Chen et al 2004).…”

“…Lung is considered to be the most sensitive site for arsenic toxicity (Chen et al 2004). Arsenite (AsO 2 ¡ ) causes malignant transformation of various cultured cells, including human keratinocytes and small airway epithelial cells (Wen et al 2008). Although evidence of the carcinogenicity of arsenic in humans is strong, the molecular mechanisms by which it causes tumorigenesis are poorly understood.…”