Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987, USA.
Environ Health Perspect. 2012 Apr;120(4):547-53. doi: 10.1289/ehp.1104179. Epub 2012 Jan 6.
Hexavalent chromium [Cr(VI)] is recognized as a human carcinogen via inhalation. However, the molecular mechanisms by which Cr(VI) causes cancers are not well understood.
We evaluated cyclooxygenase-2 (COX-2) expression and the signaling pathway leading to this induction due to Cr(VI) exposure in cultured cells.
We used the luciferase reporter assay and Western blotting to determine COX-2 induction by Cr(VI). We used dominant negative mutant, genetic knockout, gene knockdown, and chromatin immunoprecipitation approaches to elucidate the signaling pathway leading to COX-2 induction.
We found that Cr(VI) exposure induced COX-2 expression in both normal human bronchial epithelial cells and mouse embryonic fibroblasts in a concentration- and time-dependent manner. Deletion of IKKβ [inhibitor of transcription factor NFκB (IκB) kinase β; an upstream kinase responsible for nuclear factor κB (NFκB) activation] or overexpression of TAM67 (a dominant-negative mutant of c-Jun) dramatically inhibited the COX-2 induction due to Cr(VI), suggesting that both NFκB and c-Jun/AP-1 pathways were required for Cr(VI)-induced COX-2 expression. Our results show that p65 and c-Jun are two major components involved in NFκB and AP-1 activation, respectively. Moreover, our studies suggest crosstalk between NFκB and c-Jun/AP-1 pathways in cellular response to Cr(VI) exposure for COX-2 induction.
We demonstrate for the first time that Cr(VI) is able to induce COX-2 expression via an NFκB/c-Jun/AP-1-dependent pathway. Our results provide novel insight into the molecular mechanisms linking Cr(VI) exposure to lung inflammation and carcinogenesis.
六价铬（Cr(VI)）已被确认为通过吸入途径致癌的物质。然而，Cr(VI)导致癌症的分子机制尚未完全阐明。
我们评估了细胞培养中 Cr(VI)暴露引起的环氧合酶-2（COX-2）表达及其诱导的信号通路。
我们使用荧光素酶报告基因检测和 Western blot 来确定 Cr(VI)诱导的 COX-2 表达。我们使用显性失活突变体、基因敲除、基因敲低和染色质免疫沉淀方法来阐明导致 COX-2 诱导的信号通路。
我们发现 Cr(VI)暴露以浓度和时间依赖的方式诱导正常人类支气管上皮细胞和小鼠胚胎成纤维细胞中 COX-2 的表达。IKKβ（NFκB 转录因子抑制剂激酶β；负责核因子 κB（NFκB）激活的上游激酶）的缺失或 TAM67（c-Jun 的显性失活突变体）的过表达显著抑制了 Cr(VI)诱导的 COX-2 表达，表明 NFκB 和 c-Jun/AP-1 通路都需要 Cr(VI)诱导 COX-2 表达。我们的结果表明，p65 和 c-Jun 分别是参与 NFκB 和 AP-1 激活的两个主要成分。此外，我们的研究表明，在细胞对 Cr(VI)暴露的反应中，NFκB 和 c-Jun/AP-1 通路之间存在串扰，以诱导 COX-2 的表达。
我们首次证明 Cr(VI)能够通过 NFκB/c-Jun/AP-1 依赖途径诱导 COX-2 的表达。我们的研究结果为 Cr(VI)暴露与肺部炎症和致癌作用之间的分子机制提供了新的见解。
