Protective effect of glucocorticoid receptor against lung inflammation induced by nicotine-derived nitrosamine ketone is mediated by suppression of the ROS-mediated cyclooxygenase-2/prostaglandin E2 pathway in human distal lung epithelial A549 cells.

Cigarette smoking is a significant risk factor for lung cancer. The cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway is a well-established key player in inflammation and tumorigenesis, both of which are linked to cigarette smoking. Nevertheless, the function of glucocorticoid receptors (GR) in the context of the COX-2/PGE2 pathway induced by nicotine-derived nitrosamine ketones (NNK) remains to be elucidated. The NNK-induced increase in COX-2 expression and PGE2 production was inhibited by glucocorticoids, and this effect was antagonized by the GR antagonist, RU38486. Notably, the induction of COX-2 by NNK correlated with NNK's ability to increase reactive oxygen species (ROS). The ROS scavenger N-acetylcysteine inhibited the NNK-induced increase in COX-2 mRNA levels and promoter activity. Furthermore, dexamethasone significantly inhibited NNK-induced cell invasion. Conclusively, the data collectively indicate that NNK-induced ROS activates the COX-2/PGE2 pathway and cell invasion in lung cancer cells. These findings elucidate the pathophysiological connection between NNK, GR, inflammatory responses, and cell metastasis.