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

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-beta(2)) and induce cyclooxygenase-2 (COX-2) expression. Restoration of RAR-beta(2) 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-beta(2)-mediated suppression of COX-2 expression using BPDE as a tool. We found that BPDE-induced COX-2 expression was through inhibition of RAR-beta(2) 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-beta(2) did not respond to BPDE for induction of COX-2. BPDE was also unable to induce COX-2 expression after RAR-beta(2) expression was manipulated in these esophageal cancer cells. Furthermore, BPDE induced time-dependent methylation of RAR-beta(2) gene promoter in esophageal cancer cells. Transfection of RAR-beta(2) expression vector into esophageal cancer cells suppressed expression of EGFR, Erk1/2 phosphorylation, c-Jun, and COX-2. In addition, co-treatment of RAR-beta(2)-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-beta(2) results in COX-2 induction and restoration of RAR-beta(2) expression reduces COX-2 protein in esophageal cancer cells, thereby further supporting our previous finding that RAR-beta(2) plays an important role in suppressing esophageal carcinogenesis.

• Authors: Shumei Song, Scott M Lippman, Yiyu Zou, Xiaofeng Ye, Jaffer A Ajani, Xiao-Chun Xu
• Journal: Oncogene (Oncogene) Vol. 24 Issue 56 Pg. 8268-76 (Dec 15 2005) ISSN: 0950-9232 [Print] England
• PMID: 16170369 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Oncogene (2005) 24, 8268-8276. doi:10.1038/sj.onc.1208992; published online 19 September 2005.

Chemical References

• Butadienes
• Nitriles
• Receptors, Retinoic Acid
• Transcription Factor AP-1
• U 0126
• retinoic acid receptor beta
• 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
• Cyclooxygenase 2
• Extracellular Signal-Regulated MAP Kinases
• JNK Mitogen-Activated Protein Kinases

Topics

• 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide (pharmacology)
• Animals
• Butadienes (pharmacology)
• Cell Line, Transformed
• Cell Line, Tumor
• Cyclooxygenase 2 (biosynthesis, genetics)
• DNA Methylation (drug effects)
• Enzyme Induction (drug effects, genetics)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, biosynthesis, genetics)
• JNK Mitogen-Activated Protein Kinases (biosynthesis, genetics)
• Mice
• Mice, Nude
• Multigene Family (physiology)
• Nitriles (pharmacology)
• Phosphorylation
• Promoter Regions, Genetic (drug effects)
• Receptors, Retinoic Acid (antagonists & inhibitors, biosynthesis, physiology)
• Transcription Factor AP-1 (physiology)