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J. Biol. Chem., Vol. 281, Issue 51, 39022-39032, December 22, 2006

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Nickel Compounds Render Anti-apoptotic Effect to Human Bronchial Epithelial Beas-2B Cells by Induction of Cyclooxygenase-2 through an IKK/p65-dependent and IKK- and p50-independent Pathway^*

Jin Ding, Xinhai Zhang, Jingxia Li, Lun Song, Weiming Ouyang, Dongyun Zhang, Caifang Xue, Max Costa, J. Andrés Meléndez^¶, and Chuanshu Huang¹

From the Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987, the Department of Etiology, Fourth Military Medical University, 17 Changlexi Road, Xi'an, Shaanxi 710032, China, and the ^¶Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208

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-KM, a kinase inactive mutant of IKK, blocked NF-B activation and COX-2 induction by nickel compounds, indicating that activated NF-B may be a mediator for COX-2 induction. To further explore the contribution of the NF-B pathway in COX-2 induction and in protection from nickel exposure, mouse embryonic fibroblasts deficient in IKK, IKK, p65, and p50 were analyzed. Loss of IKK impaired COX-2 induction by nickel exposure, whereas knockout of IKK had a marginal effect. Moreover, the NF-B p65, and not the p50 subunit, was critical for nickel-induced COX-2 expression. In addition, a deficiency of IKK 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-B activation and COX-2 expression. Collectively, our results demonstrate that COX-2 induction by nickel compounds occurs via an IKK/p65 NF-B-dependent but IKK- and p50-independent pathway and plays a crucial role in antagonizing nickel-induced cell apoptosis in Beas-2B cells.

Received for publication, May 18, 2006 , and in revised form, September 6, 2006.

^* This work was supported by Grants R01 CA112557, R01 CA094964, and R01 CA103180 from NCI/National Institutes of Health (NIH) and R01 ES012451 from NIEHS/NIH. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Nelson Inst. of Environmental Medicine, New York University School of Medicine, 57 Old Forge Rd., Tuxedo, NY 10987. Tel.: 845-731-3519; Fax: 845-351-2320; E-mail: chuanshu{at}env.med.nyu.edu.

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