Differential effects of polycyclic aromatic hydrocarbons on transactivation of AP-1 and NF-kappaB in mouse epidermal cl41 cells

Mol Carcinog. 2004 Jun;40(2):104-15. doi: 10.1002/mc.20020.


Polycyclic aromatic hydrocarbons (PAHs) and their derivatives, such as benzo[a]pyrene (B[a]P), (+/-)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (B[a]PDE), and 5-methylchrysene-1,2-diol-3,4-epoxide (5-MCDE), are complete carcinogens. However, the tumor promotion effects of PAHs remain unclear. We therefore investigated the possible activation of activator protein-1 (AP-1) and nuclear factor-kappaB (NFkappaB) in mouse epidermal Cl41 cells after different PAHs treatments, including B[a]P, B[a]PDE, chrysene-1,2-diol-3,4-epoxid (CDE), and 5-MCDE. The results showed that B[a]PDE and 5-MCDE were able to activate AP-1 and NF-kappaB, whereas B[a]P showed only marginal effect on AP-1 activation, and B[a]P and CDE had no effect on NF-kappaB activation. Treatment with either B[a]PDE or 5-MCDE also resulted in mitogen-activated protein kinases (MAPKs) activation as well as inhibitory subunit kappa-B (IkappaBalpha) phosphorylation and degradation, whereas B[a]P and CDE had no effect. Pretreatment with PD98059, a specific inhibitor for extracellular signal-regulated protein kinases (ERKs) upstream kinase MEK1/2, or SB202190, a p38 kinase inhibitor, resulted in a dramatic inhibition of B[a]PDE-induced AP-1 transactivation. In addition, B[a]PDE-induced AP-1 activation was also inhibited by overexpressing a dominant negative mutant of JNK1 in the cells. All these suggest ERKs, c-jun N-terminal kinases (JNKs), and p38 kinase signal transduction pathways are required for AP-1 induction by B[a]PDE. Taken together, B[a]PDE and 5-MCDE are the active compounds of PAHs to initiate signaling pathways. Considering the important roles of AP-1 and NF-kappaB in tumor promotion, we speculated the activation of AP-1 and NF-kappaB by B[a]PDE and 5-MCDE may involve in their or their parent compounds' tumor promotion effects. This study may help in better understanding the tumor promotion effects of PAHs.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / toxicity
  • Animals
  • Benzo(a)pyrene / toxicity
  • Carcinogens / toxicity*
  • Cells, Cultured
  • Chrysenes / toxicity
  • Enzyme Inhibitors / pharmacology
  • Epidermal Cells
  • Epidermis / drug effects*
  • Epidermis / metabolism
  • Flavonoids / pharmacology
  • I-kappa B Proteins / drug effects
  • I-kappa B Proteins / metabolism
  • Imidazoles / pharmacology
  • JNK Mitogen-Activated Protein Kinases
  • Mice
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / drug effects*
  • NF-kappa B / metabolism
  • Phosphorylation
  • Polycyclic Aromatic Hydrocarbons / toxicity*
  • Pyridines / pharmacology
  • Signal Transduction
  • Transcription Factor AP-1 / drug effects*
  • Transcription Factor AP-1 / metabolism
  • Transcriptional Activation / drug effects


  • Carcinogens
  • Chrysenes
  • Enzyme Inhibitors
  • Flavonoids
  • I-kappa B Proteins
  • Imidazoles
  • NF-kappa B
  • Polycyclic Aromatic Hydrocarbons
  • Pyridines
  • Transcription Factor AP-1
  • Benzo(a)pyrene
  • 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
  • chrysene,2-diol-3,4-epoxide-1
  • 1,2-dihydroxy-epoxy-1,2,3,4-tetrahydro-5-methylchrysene
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one