title: Nickel compounds render anti-apoptotic effect to human bronchial epithelial Beas-2B cells by induction of cyclooxygenase-2 through an IKKbeta/p65-dependent and IKKalpha- and p50-independent pathway.
abstract: The carcinogenicity of nickel compounds has been well documented both in vitro and in vivo; however, the molecular mechanisms by which nickel compounds cause cancers are far from understood. Because suppression of apoptosis is thought to contribute to carcinogenesis, we investigated the mechanisms implicated in nickel-induced anti-apoptotic effect in human bronchial epithelial (Beas-2B) cells. We found that exposure of Beas-2B cells to nickel compounds resulted in increased cyclooxygenase-2 (COX-2) expression and that small interfering RNA (siCOX-2) knockdown of COX-2 expression resulted in increased cell sensitivity to nickel-triggered cell apoptosis, demonstrating that COX-2 induction has an anti-apoptotic effect on Beas-2B cells. Overexpression of IKKbeta-KM, a kinase inactive mutant of IKKbeta, blocked NF-kappaB activation and COX-2 induction by nickel compounds, indicating that activated NF-kappaB may be a mediator for COX-2 induction. To further explore the contribution of the NF-kappaB pathway in COX-2 induction and in protection from nickel exposure, mouse embryonic fibroblasts deficient in IKKbeta, IKKalpha, p65, and p50 were analyzed. Loss of IKKbeta impaired COX-2 induction by nickel exposure, whereas knockout of IKKalpha had a marginal effect. Moreover, the NF-kappaB p65, and not the p50 subunit, was critical for nickel-induced COX-2 expression. In addition, a deficiency of IKKbeta or p65 rendered cells more sensitive to nickel-induced apoptosis as compared with those in wild type cells. Finally, it was shown that reactive oxygen species H(2)O(2) were involved in both NF-kappaB activation and COX-2 expression. Collectively, our results demonstrate that COX-2 induction by nickel compounds occurs via an IKKbeta/p65 NF-kappaB-dependent but IKKalpha- and p50-independent pathway and plays a crucial role in antagonizing nickel-induced cell apoptosis in Beas-2B cells.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Ding
authors.forename: Xinhai
authors.initials: X
authors.lastname: Zhang
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.forename: Lun
authors.initials: L
authors.lastname: Song
authors.forename: Weiming
authors.initials: W
authors.lastname: Ouyang
authors.forename: Dongyun
authors.initials: D
authors.lastname: Zhang
authors.forename: Caifang
authors.initials: C
authors.lastname: Xue
authors.forename: Max
authors.initials: M
authors.lastname: Costa
authors.forename: J Andrés
authors.initials: JA
authors.lastname: Meléndez
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001980:Bronchi / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009532:Nickel / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D009532:Nickel; D051546:Cyclooxygenase 2; D051550:I-kappa B Kinase