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

Abstract

Hypoxia-inducible factors (HIFs), which consist of α and β subunits, are transcription factors involved in regulation of a variety of cellular functions. By blocking the function of the tumor suppressor p53, over-expressions of HIFs are linked to carcinogenesis and tumor progression. Inorganic arsenic, a ubiquitous environmental contaminant, is associated with an increased risk of cancer. Although there are several hypotheses regarding arsenic-induced carcinogenesis, the mechanism of action remains obscure. We have shown that long-term exposure of human bronchial epithelial (HBE) cells to a low level of arsenite increases their proliferation rate and anchorage-independent growth. When introduced into nude mice, the transformed cells are tumorigenic. The present report demonstrates that, with increased time of exposure to arsenite, there is more increased expression of HIF-2α, but not HIF-1α. These factors are known to have different functions, and, in some cases, opposite effects. Arsenite induces accumulation of HIF-2α by inhibiting its degradation through the ubiquitin-mediated proteasome pathway. HIF-2α knockdown, but not HIF-1α knockdown, increases the activation of p53. Finally, inhibition of HIF-2α blocks arsenite-induced proliferation and malignant transformation. Thus, our studies show that blockade of p53 function by inhibiting the ubiquitin-mediated proteasome degradation of HIF-2α, but not that of HIF-1α, is involved in arsenite-induced proliferation and neoplastic transformation of HBE cells.

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. Anchorage-independent growth is a common characteristic of transformed cells, and it is usually evaluated by soft agar cloning assay (Cox and Der, 1994).…”

The lncRNA MALAT1, acting through HIF-1α stabilization, enhances arsenite-induced glycolysis in human hepatic L-02 cells

“…Our previous investigations have shown that, in human bronchial epithelial cells and human embryonic lung fibroblasts, arsenite decreases p53 levels and increases NF-κB expression [10,23]. We tested the possibility that arsenite affects cellular metabolism by accelerating glycolysis.…”

“…HIFs are sensitive to environmental factors, especially arsenite, and, under normoxic conditions, they are involved in the regulation of a variety of cellular functions and thereby contribute to various malignancies [8,9]. HIF-α binds to hypoxia response elements (HREs) of target genes for vascular endothelial growth factor [10], glycolytic enzymes [11], and glucose transporters [12,13], which are related to aspects of cancer growth, including proliferation, angiogenesis, and glycolysis. HIF-α expression is also increased, however, under certain normoxic conditions.…”

Arsenic: an ancient toxicant of continuous public health impact, from Iceman Ötzi until now

“…In this issue of Archives of Toxicology, authors from leading governmental US institutions (NTP, NIEHS, NCI) present a study that raises the serious concern of trans-placental carcinogenesis by a specific As compound, methylarsenous acid (Tokar et al 2012). Against such a background, the priority of current research into mechanisms of As-induced malignant transformation is evident (Xu et al 2012).…”