Activation of both nuclear factor of activated T cells and inhibitor of nuclear factor‐κB kinase β‐subunit‐/nuclear factor‐κB is critical for cyclooxygenase‐2 induction by benzo[a]pyrene in human bronchial epithelial cells

The carcinogenic effect of benzo[a]pyrene (B[a]P), presenting mainly in cigarette smoke and air pollution, has been well demonstrated both in vitro and in vivo . However, it is still not well understood how B[a]P facilitates pulmonary carcinogenesis. To explore this, we investigated the effect of B[a]P on the induction of cyclooxygenase‐2 (COX‐2), a critical enzyme implicated in inflammation and cancer development, as well as upstream signaling pathways leading to its expression in human bronchial epithelial cells (Beas‐2B). We found that exposure of Beas‐2B to B[a]P caused significant COX‐2 induction at both the transcriptional and protein levels. B[a]P also switched on the nuclear factor of activated T cells (NFAT) and nuclear factor κB (NF‐κB) signaling pathways. B[a]P‐induced COX‐2 expression was significantly blocked by inhibition of the NFAT pathway, and impairment of the NF‐κB signaling pathway by ectopic expression of an inhibitor of nuclear factor‐κB kinase β‐subunit (IKKβ) kinase inactive mutant (IKKβ‐KM) also dramatically inhibited COX‐2 induction. The IKKβ/NF‐κB‐dependent COX‐2 induction was further confirmed in mouse embryonic fibroblasts with IKKβ deficiency (IKKβ −/– ) and in those that expressed reconstituted IKKβ. However, activation of the NFAT and NF‐κB signaling pathways by B[a]P were independent of each other, as blocking one signaling pathway didn't interrupt the activation of the other one. Mutation of either NFAT or NF‐κB binding sites significantly blocked COX‐2 promoter induction by B[a]P. Taken together, these data indicate that exposure of Beas‐2B to B[a]P can upregulate COX‐2 expression by increasing its transcription, which requires activation of both the NFAT and NF‐κB signaling pathways. ( Cancer Sci 2007; 98: 1323–1329)