Benzo[a]pyrene diol-epoxide (B[a]PDE) upregulates COX-2 expression through MAPKs/AP-1 and IKKβ/NF-κB in mouse epidermal Cl41 cells

Weiming Ouyang, Qian Ma, Jingxia Li, Dongyun Zhang, Jin Ding, Yi Huang, Mingzhao M. Xing, Chuanshu Huang

Research output: Contribution to journalArticle

Abstract

Benzo[α]pyrene-7,8-diol-9,10-epoxide (B[a]PDE), the major metabolite of benzo[a]pyrene (B[a]P), shows an ultimate complete carcinogen in various animals and is a causative agent for human cancers. However, its effects on the activation of signal pathways and the expression of genes involved in its carcinogenic effect remain largely unknown. In this study, the effects of B[a]PDE on induction of cyclooxygenase (COX)-2 and the signal pathways leading to the induction were investigated. Treatment of mouse epidermal Cl41 cells with B[a]PDE caused an increase in the expression of COX-2 at both transcription and protein levels, while its parental compound B[a]P did not show significant inductive effect. The COX-2 induction by B[a]PDE was dependent on the activation of mitogen-activated protein kinases (MAPK)s/activation protein (AP)-1 pathway, because inhibition of AP-1 by either overexpression of TAM67 (dominant negative mutant of c-jun), or pretreatment of cells with PD98059 (MEK1/2-ERKs pathway inhibitor) or SB202190 (p38K inhibitor), markedly inhibited B[a]PDE-induced COX-2 expression. In addition, impairment of NF-κB pathway by either NEMO-BDBP (an NF-κB specific inhibitor) or IκB kinase (IKK)β-KM (dominant negative mutant of IKKβ) also caused marked reduction of COX-2 induction by B[a]PDE. In contrast, inhibition of nuclear factor of activated T cells (NFAT) with FK506, did not show any effect on B[a]PDE-induced COX-2 expression. Collectively, these data indicate that exposure of Cl41 cells to B[a]PDE can induce COX-2 expression by increasing its transcription, which requires the activation of MAPKs/AP-1 and IKKβ/NF-κB pathways, but not NFAT pathway. In view of the importance of COX-2 in carcinogenesis, we anticipate that the induction of COX-2 by B[a]PDE may coordinate its mutagenic effects to facilitate the development of skin cancer.

Original languageEnglish (US)
Pages (from-to)32-41
Number of pages10
JournalMolecular Carcinogenesis
Volume46
Issue number1
DOIs
StatePublished - Jan 2007

Keywords

  • B[a]PDE
  • COX-2
  • Carcinogenesis
  • Signal pathway

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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