title: A cross-talk between NFAT and NF-κB pathways is crucial for nickel-induced COX-2 expression in Beas-2B cells.
abstract: Cyclooxygenase-2 (COX-2) is a critical enzyme implicated in chronic inflammation-associated cancer development. Our studies have shown that the exposure of Beas-2B cells, a human bronchial epithelial cell line, to lung carcinogenic nickel compounds results in increased COX-2 expression. However, the signaling pathways leading to nickel-induced COX-2 expression are not well understood. In the current study, we found that the exposure of Beas-2B cells to nickel compounds resulted in the activation of both nuclear factor of activated T cell (NFAT) and nuclear factor-κB (NF-κB). The expression of COX-2 induced upon nickel exposure was inhibited by either a NFAT pharmacological inhibitor or the knockdown of NFAT3 by specific siRNA. We further found that the activation of NFAT and NF-κB was dependent on each other. Since our previous studies have shown that NF-κB activation is critical for nickel-induced COX-2 expression in Beas-2B cells exposed to nickel compounds under same experimental condition, we anticipate that there might be a cross-talk between the activation of NFAT and NF-κB for the COX-2 induction due to nickel exposure in Beas-2B cells. Furthermore, we showed that the scavenging of reactive oxygen species (ROS) by introduction of mitochondrial catalase inhibited the activation of both NFAT and NF-κB, and the induction of COX-2 due to nickel exposure. Taken together, our results defining the evidence showing a key role of the cross-talk between NFAT and NF-κB pathways in regulating nickel-induced COX-2 expression, further provide insight into the understanding of the molecular mechanisms linking nickel exposure to its lung carcinogenic effects.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
authors.forename: Tongjian
authors.initials: T
authors.lastname: Cai
authors.forename: Xueyong
authors.initials: X
authors.lastname: Li
authors.forename: Jin
authors.initials: J
authors.lastname: Ding
authors.forename: Wenjing
authors.initials: W
authors.lastname: Luo
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002374:Catalase / Q000378:metabolism; D002460:Cell Line; D018890:Chemoprevention; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009532:Nickel / Q000633:toxicity*; D009994:Osmolar Concentration; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D002274:Carcinogens, Environmental; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494010:NFATC4 protein, human; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D009532:Nickel; D002374:Catalase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human