Arachidonic acid suppresses hepatic cell growth through ROS‐mediated activation of transglutaminase

We previously reported a profound augmentation in the hepatic levels of a pro‐inflammatory precursor, arachidonic acid (AA), during liver tumorigenesis. Here, we report a critical role of the induced reactive oxygen species (ROS)‐mediated cellular activation of a protein cross‐linking enzyme, transglutaminase 2 (TG2), in liver injury by AA. In cultures of hepatic cells, AA dose‐dependently suppressed cell growth, which accompanied the induced nuclear accumulation of TG2, as demonstrated in EGFP‐tagged, TG2‐overexpressing hepatic cells. A chemical inhibitor/shRNA that acts against TG2 prevented AA‐mediated cell growth suppression. In addition, AA provoked significant production of ROS, and antioxidants blocked AA‐induced activation of nuclear TG2 and hepatic cell growth suppression. We propose that AA‐mediated oxidative stress and TG2 transamidase activity might contribute to chronic liver injury and inflammation and thereby serve as potential therapeutic targets for the chemoprevention of hepatocellular carcinoma.