Abstract

Arsenite is a well known metalloid human carcinogen, and epidemiological evidence has demonstrated its association with the increased incidence of lung cancer. However, the mechanism involved in its lung carcinogenic effect remains obscure. The current study demonstrated that exposure of human bronchial epithelial cells (Beas-2B) to arsenite resulted in a marked induction of cyclooxygenase (COX)-2, an important mediator for inflammation and tumor promotion. Exposure of the Beas-2B cells to arsenite also led to significant transactivation of nuclear factor of activated T-cells (NFAT), but not activator protein-1 (AP-1) and NFkappaB, suggesting that NFAT, rather than AP-1 or NFkappaB, is implicated in the responses of Beas-2B cells to arsenite exposure. Furthermore, we found that inhibition of the NFAT pathway by either chemical inhibitors, dominant negative mutants of NFAT, or NFAT3 small interference RNA resulted in the impairment of COX-2 induction and caused cell apoptosis in Beas-2B cells exposed to arsenite. Site-directed mutation of two putative NFAT binding sites between-111 to +65 in the COX-2 promoter region eliminated the COX-2 transcriptional activity induced by arsenite, confirming that those two NFAT binding sites in the COX-2 promoter region are critical for COX-2 induction by arsenite. Moreover, knockdown of COX-2 expression by COX-2-specific small interference RNA also led to an increased cell apoptosis in Beas-2B cells upon arsenite exposure. Together, our results demonstrate that COX-2 induction by arsenite is through NFAT3-dependent and AP-1- or NFkappaB-independent pathways and plays a crucial role in antagonizing arsenite-induced cell apoptosis in human bronchial epithelial Beas-2B cells.

Highlights

  • Arsenic is an environmental toxin widely distributed in water, food, air, and soil [1]

  • Our results demonstrate that COX-2 induction by arsenite is through NFAT3-dependent and activator protein-1 (AP-1)- or nuclear factor ␬B (NF␬B)-independent pathways and plays a crucial role in antagonizing arsenite-induced cell apoptosis in human bronchial epithelial Beas-2B cells

  • The present study documents that arsenite can markedly induce COX-2 expression through the calcineurin/nuclear factor of activated T-cells (NFAT)-dependent pathway in human bronchial epithelial Beas-2B cells, and we demonstrate that elevated COX-2 protein expression mediates the protection of Beas-2B cells from apoptosis caused by arsenite

Read more

Summary

Introduction

Arsenic is an environmental toxin widely distributed in water, food, air, and soil [1]. Previous studies have shown that environmental and occupational exposure to arsenite is associated with an increased risk of human cancers, including skin and lung cancers. It has been reported that arsenite exposure can stimulate COX-2 expression through activating the nuclear factor ␬B (NF␬B) pathway in endothelial cells [17]. Whether arsenite is able to induce COX-2 expression in human bronchial epithelial cells and, if it does, which signaling pathway mediates its induction, as well as what the role of COX-2 is in cell responses to arsenite exposure, have not yet been investigated. The present study documents that arsenite can markedly induce COX-2 expression through the calcineurin/NFAT-dependent pathway in human bronchial epithelial Beas-2B cells, and we demonstrate that elevated COX-2 protein expression mediates the protection of Beas-2B cells from apoptosis caused by arsenite

Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call