Academic journal article Environmental Health Perspectives

Hexavalent Chromium Cr(VI) Up-Regulates COX-2 Expression through an NF[kappa]B/c-Jun/AP-1-Dependent Pathway

Academic journal article Environmental Health Perspectives

Hexavalent Chromium Cr(VI) Up-Regulates COX-2 Expression through an NF[kappa]B/c-Jun/AP-1-Dependent Pathway

Article excerpt

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 IKK[beta] [inhibitor of transcription factor NF[kappa]B (I[kappa]B) kinase [beta]; an upstream kinase responsible for nuclear factor [kappa]B (NF[kappa]B) 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 NF[kappa]B 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 NF[kappa]B and AP-1 activation, respectively. Moreover, our studies suggest crosstalk between NF[kappa]B 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 NF[kappa]B/c-Jun/AP-1-dependent pathway. Our results provide novel insight into the molecular mechanisms linking Cr(VI) exposure to lung inflammation and carcinogenesis.

KEY WORDS: AP-1, chromium, c-Jun, COX-2, NF[kappa]B. Environ Health Perspect 120:547-553 (2012). http://dx.doi.org/10.1289/ehp.1104179 [Online 6 January 2012]

Chromium (Cr) is a ubiquitous metal found in animals, plants, rocks, soil, and air (Hill et al. 2008). Exposure to hexavalent chromium [Cr(VI)] occurs in multiple occupational environments, and the approximate daily absorbed dose of Cr(VI) is 83-1,700 [micro]g/kg/day (Beveridge 2010). The International Agency for Research on Cancer (1980) has classified Cr(VI) as a known human carcinogen. Previous in vivo studies strongly indicated that there is an association between Cr(VI) exposure and airway inflammation and lung carcinogenesis (Beaver et al. 2009a, 2009b; Zeidler-Erdely et al. 2008). However, the molecular mechanisms by which Cr(VI) induces lung inflammation and cancers are not yet well understood.

Prostaglandin (PG) is an important mediator at all stages of cancer development (Menter 2002). Cyclooxygenase (COX) is the rate-limiting enzyme in the synthesis of PGs (Rao et al. 2004). The COX enzyme system is composed of two isoenzymes: COX-1, the constitutive isoform, and COX-2, the inducible protein (Davies et al. 2002). COX-2 can undergo rapid induction in response to many factors, such as growth factors and cytokines (Kirschenbaum et al. 2001), and is highly expressed in a variety of human cancers and cancer cell lines (Liao and Milas 2004).COX-2 overexpression is associated with more aggressive biological tumor behaviors (Liao and Milas 2004), and the inhibition of COX-2 has been regarded as an effective anticancer strategy (Davies et al. 2002). Thus, identification of the potential involvement of COX-2 and molecular mechanisms responsible for COX-2 induction due to Cr(VI) exposure will provide significant insight into understanding Cr(VI) lung inflammatory and carcinogenic effects. In the present study, we investigated the potential effects of Cr(VI) on COX-2 expression and molecular mechanisms leading to this induction in cell culture models.

Materials and Methods

Cell culture and reagents. Mouse embryonic fibroblasts (MEFs) were cultured in 37[degrees]C with 5% [CO. …

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