Induction of cyclooxygenase-2 by benzo[a]pyrene diol epoxide through inhibition of retinoic acid receptor-beta 2 expression.
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.
Song
Shumei
S
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1360, Houston, TX 77030, USA.
Lippman
Scott M
SM
Zou
Yiyu
Y
Ye
Xiaofeng
X
Ajani
Jaffer A
JA
Xu
Xiao-Chun
XC
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000494:pharmacology*; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D005810:Multigene Family / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000502:physiology
D002070:Butadienes; D009570:Nitriles; D018168:Receptors, Retinoic Acid; D018808:Transcription Factor AP-1; C113580:U 0126; C082925:retinoic acid receptor beta; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases