Hexavalent Chromium Cr(VI) Up-Regulates COX-2 Expression through an NFκB/c-Jun/AP-1-Dependent Pathway.

Autor:	Zuo, Zhenghong^1,2, Cai, Tongjian¹, Li, Jingxia¹, Zhang, Dongyun¹, Yu, Yonghui¹, Huang, Chuanshu¹ chuanshu.huang@nyumc.org
Předmět:	Hexavalent chromium Animal experimentation *Carcinogens Biological assay Cell culture Cellular signal transduction Chemiluminescence assay Diagnosis Genetic techniques Mice Oxidoreductases Polymerase chain reaction Precipitin reaction Research funding T-test (Statistics) Western immunoblotting Descriptive statistics
Zdroj:	Environmental Health Perspectives. Apr2012, Vol. 120 Issue 4, p547-553. 7p. 1 Diagram, 4 Graphs.
Abstrakt:	Background: 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. Objectives: We evaluated cyclooxygenase-2 (COX-2) expression and the signaling pathway leading to this induction due to Cr(VI) exposure in cultured cells. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]
Databáze:	GreenFILE
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