Naturally occurring phenolic acids modulate TPA-induced activation of EGFR, AP-1, and STATs in mouse epidermis

Nutr Cancer. 2014;66(2):308-14. doi: 10.1080/01635581.2014.864419. Epub 2013 Dec 31.


Epidermal growth factor receptor (EGFR) plays an important role in epithelial carcinogenesis and appears to be involved in STATs activation. In this study we investigated the possible interference of naturally occurring phenolic acids with EGFR, activator protein-1 (AP-1), and signal transducers and activators of transcription (STATs) pathways activated by topical application of tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Balb/c mice epidermis. Pretreatment with tannic or chlorogenic acid resulted in a significant decrease in the phosphorylation of EGFR Y-1068 and Y-1173 tyrosine residues, which was accompanied by reduced activation of AP-1. Tannic acid decreased also the c-Jun AP-1 subunit level and binding to TPA response element (TRE) (3- and 2-fold in comparison with TPA-treated group respectively). Simultaneous reduction of JNK activity might be responsible for reduced activation of AP-1. In contrast to these more complex phenolics, protocatechuic acid increased the activity of JNK and was also the most efficient inhibitor of STATs activation. These results indicate that naturally occurring phenolic acids, by decreasing EGFR, AP-1, and STATs activation, may modulate other elements both upstream and downstream in these pathways and thus inhibit the tumor development. Although more complex phenolics affect mainly the EGFR/AP-1 pathway, STATs seem to be the most important targets for simple compounds, such as protocatechuic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogens / administration & dosage
  • Carcinogens / antagonists & inhibitors
  • Carcinogens / toxicity
  • Chlorogenic Acid / pharmacology
  • Epidermis / drug effects*
  • Epidermis / metabolism
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Female
  • Hydroxybenzoates / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Phosphorylation
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction
  • Tannins / pharmacology
  • Tetradecanoylphorbol Acetate / administration & dosage
  • Tetradecanoylphorbol Acetate / antagonists & inhibitors
  • Tetradecanoylphorbol Acetate / toxicity*
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism*


  • Carcinogens
  • Hydroxybenzoates
  • STAT3 Transcription Factor
  • STAT5 Transcription Factor
  • Stat3 protein, mouse
  • Stat5a protein, mouse
  • Stat5b protein, mouse
  • Tannins
  • Transcription Factor AP-1
  • Chlorogenic Acid
  • protocatechuic acid
  • EGFR protein, mouse
  • ErbB Receptors
  • phenolic acid
  • Tetradecanoylphorbol Acetate