Nickel compounds render anti-apoptotic effect to human bronchial epithelial Beas-2B cells by induction of cyclooxygenase-2 through an IKKβ/p65-dependent and IKKα- and p50-independent pathway
Nickel compounds render anti-apoptotic effect to human bronchial epithelial Beas-2B cells by induction of cyclooxygenase-2 through an IKKβ/p65-dependent and IKKα- and p50-independent pathway
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DOI：
10.1074/jbc.m604798200
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发表时间：
2006-12-22
影响因子：
4.8
通讯作者：
Huang, Chuanshu
中科院分区：
文献类型：
--
作者：
Ding, Jin;Zhang, Xinhai;Huang, Chuanshu
镍化合物的致癌性在体外和体内均已得到充分证明；然而，镍化合物致癌的分子机制尚不清楚。由于细胞凋亡的抑制被认为有助于致癌，因此我们研究了镍诱导的人支气管上皮 (Beas-2B) 细胞抗凋亡作用的机制。我们发现Beas-2B细胞暴露于镍化合物会导致环氧合酶-2（COX-2）表达增加，并且COX-2表达的小干扰RNA（siCOX-2）敲低导致细胞对镍触发的细胞凋亡的敏感性增加，证明COX-2诱导对Beas-2B细胞具有抗凋亡作用。 IKK beta-KM（IKK beta 的激酶失活突变体）的过表达可阻断镍化合物对 NF-κ B 的激活和 COX-2 的诱导，表明激活的 NF-κ B 可能是 COX-2 诱导的介质。为了进一步探讨 NF-κ B 通路在 COX-2 诱导和镍暴露保护中的作用，对 IKK beta、IKK beta、p65 和 p50 缺陷的小鼠胚胎成纤维细胞进行了分析。 IKK beta 的缺失会损害镍暴露对 COX-2 的诱导，而 IKK beta 的敲除则具有边际效应。此外，NF-kappa B p65，而不是 p50 亚基，对于镍诱导的 COX-2 表达至关重要。此外，与野生型细胞相比，IKK beta 或 p65 的缺陷使细胞对镍诱导的细胞凋亡更加敏感。最后，研究表明活性氧 H2O2 参与 NF-kappa B 激活和 COX-2 表达。总的来说，我们的结果表明，镍化合物对 COX-2 的诱导是通过 IKK beta/p65 NF-kappa B 依赖性但 IKK beta 和 p50 独立途径发生的，并且在拮抗 Beas-2B 细胞中镍诱导的细胞凋亡中发挥着至关重要的作用。
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 IKK beta-KM, a kinase inactive mutant of IKK beta, blocked NF-kappa B activation and COX-2 induction by nickel compounds, indicating that activated NF-kappa B may be a mediator for COX-2 induction. To further explore the contribution of the NF-kappa B pathway in COX-2 induction and in protection from nickel exposure, mouse embryonic fibroblasts deficient in IKK beta, IKK beta, p65, and p50 were analyzed. Loss of IKK beta impaired COX-2 induction by nickel exposure, whereas knockout of IKK beta had a marginal effect. Moreover, the NF-kappa B p65, and not the p50 subunit, was critical for nickel-induced COX-2 expression. In addition, a deficiency of IKK beta 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 H2O2 were involved in both NF-kappa B activation and COX-2 expression. Collectively, our results demonstrate that COX-2 induction by nickel compounds occurs via an IKK beta/p65 NF-kappa B-dependent but IKK beta and p50-independent pathway and plays a crucial role in antagonizing nickel-induced cell apoptosis in Beas-2B cells.