Inorganic arsenic promotes apoptosis of human immortal keratinocytes through the TGF-β1/ERK signaling pathway.

Abstract

Chronic exposure to high-dose inorganic arsenic through groundwater, air, or food remains a major environmental public health issue worldwide. Apoptosis, a method of cell death, has recently become a hot topic of research in biology and medicine. Previous studies have demonstrated that extracellular signal-regulated kinase (ERK) is related to arsenic-induced apoptosis. However, the reports are contradictory, and the knowledge of the above-mentioned mechanisms and their mutual regulation remains limited. In this study, the associations between the TGF-β1/ERK signaling pathway and arsenic-induced cell apoptosis were confirmed using the HaCaT cell model. The relative expressions of the indicators of the TGF-β1/ERK signaling pathway, apoptosis-related genes (cytochrome C, caspase-3, caspase-9, cleaved caspase-3, cleaved caspase-9, and Bax), the mitochondrial membrane potential, and the total apoptosis rate were significantly increased (P <.05), while the expression of the antiapoptosis gene Bcl-2 was significantly decreased (P <.05) in cells of the group exposed to arsenic. Moreover, the results demonstrated that the ERK inhibitor (PD98059) and TGF-β1 inhibitor (LY364947) could inhibit the activation of the ERK signaling pathway, thereby reducing the mitochondrial membrane potential, the total apoptosis rate, and the expression of pro-apoptosis-related genes in the cells, while the expression of the antiapoptosis gene Bcl-2 was significantly increased (P <.05). By contrast, the recombinant human TGF-β1 could promote apoptosis of the HaCaT cells by increasing the activation of the ERK signaling pathway (P <.05). These results indicate that inorganic arsenic promotes the apoptosis of human immortal keratinocytes through the TGF-β1/ERK signaling pathway.