NDMA enhances claudin-1 and -6 expression viaCYP2E1/ROS in AGS cells.

Carcinogenic N-nitroso compounds, especially N-nitroso dimethylamine, increase the risk of gastric cancer development. Cytochrome P450-2E1 metabolizes this compound, thus generating an oxidant microenvironment. We aimed to evaluate in gastric adenocarcinoma cells if its effect on CYP2E1 and ROS affects signaling pathways associated with gastric cancer oncogenesis. The impact of N- nitroso dimethylamine upon CYP2E1 and ROS activation/secretion was evaluated by the DCFDA assay protocol, TER measurements, Stat3, pSTAT3, ERK1/2, and pERK1/2 expression, claudins-1 and -6 expression, and finally mRNA values of IL-1β IL-6, IL-8 and TNFα. Our results showed that exposure to N- N-nitroso dimethylamine disrupts the regulation of Stat3 and Erk1/2, alters the expression of claudin-1 and claudin-6 tight junction proteins, and increases the secretion of pro-inflammatory cytokines. These alterations induce a continuous local inflammatory process, an event identified as a gastric cancer promoter. In summary, N-nitroso dimethylamine can disrupt cell mechanisms associated with gastric cancer oncogenesis. • NDMA exposure led to oxidative stress in AGS cells. • NDMA increased Cldn-1 and -6 expression. • NDMA increased Stat3 and ERK2 phosphorylation. • NDMA triggered transcription of pro-inflammatory cytokines. [ABSTRACT FROM AUTHOR]