Abstract
Benzo[a]pyrene diol epoxide (BPDE, a carcinogen present in tobacco smoke and environmental pollution) has been shown to suppress retinoic acid receptor-beta2 (RAR-β2) and induce cyclooxygenase-2 (COX-2) expression. Restoration of RAR-β2 inhibited growth and colony formation of esophageal cancer cells, which was correlated with COX-2 suppression. In this study, we investigated the molecular mechanisms for RAR-β2-mediated suppression of COX-2 expression using BPDE as a tool. We found that BPDE-induced COX-2 expression was through inhibition of RAR-β2 and consequently, induction of epidermal growth factor receptor (EGFR), extracellular signal-regulated protein kinases 1/2 (Erk1/2) phosphorylation, and c-Jun expression. Esophageal cancer cells that do not express RAR-β2 did not respond to BPDE for induction of COX-2. BPDE was also unable to induce COX-2 expression after RAR-β2 expression was manipulated in these esophageal cancer cells. Furthermore, BPDE induced time-dependent methylation of RAR-β2 gene promoter in esophageal cancer cells. Transfection of RAR-β2 expression vector into esophageal cancer cells suppressed expression of EGFR, Erk1/2 phosphorylation, c-Jun, and COX-2. In addition, co-treatment of RAR-β2-positive cells with BPDE and the MEK1/2 inhibitor U0126 caused little change in c-Jun and COX-2 expression. This study demonstrated that BPDE-suppressed expression of RAR-β2 results in COX-2 induction and restoration of RAR-β2 expression reduces COX-2 protein in esophageal cancer cells, thereby further supporting our previous finding that RAR-β2 plays an important role in suppressing esophageal carcinogenesis.
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Acknowledgements
This study was supported by Jerry and Maury Rubenstein Foundation and UT MD Anderson Cancer Center Multidisciplinary Research Program. We thank the Department of Scientific Publications for editing the manuscript.
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Song, S., Lippman, S., Zou, Y. et al. Induction of cyclooxygenase-2 by benzo[a]pyrene diol epoxide through inhibition of retinoic acid receptor-β2 expression. Oncogene 24, 8268–8276 (2005). https://doi.org/10.1038/sj.onc.1208992
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DOI: https://doi.org/10.1038/sj.onc.1208992
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