Induction of cyclooxygenase-2 by benzo[a]pyrene diol epoxide through inhibition of retinoic acid receptor-β2 expression

Shumei Song, Scott M. Lippman, Yiyu Zou, Xiaofeng Ye, Jaffer A. Ajani, Xiao Chun Xu

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)8268-8276
Number of pages9
Issue number56
StatePublished - Dec 15 2005


  • AP-1
  • BPDE
  • COX-2
  • Erk1/2
  • Esophageal cancer
  • RAR-β

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research


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