title: Phloretin inhibits phorbol ester-induced tumor promotion and expression of cyclooxygenase-2 in mouse skin: extracellular signal-regulated kinase and nuclear factor-κB as potential targets.
abstract: The present study investigated the effect of phloretin [2',4',6'-trihydroxy-3-(4-hydroxyphenyl)-propiophenone] on 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced cyclooxygenase-2 (COX-2) expression and tumor promotion in mouse skin and explored the underlying molecular mechanisms. Topical application of phloretin significantly inhibited 7,12-dimethylbenz[a]anthracene-initiated and TPA-promoted mouse skin carcinogenesis. Pretreatment with phloretin on the dorsal skin of mice inhibited TPA-induced COX-2 expression in a dose-dependent manner. To elucidate the molecular mechanism underlying COX-2 inhibition by phloretin, we examined its effect on TPA-induced activation of nuclear factor-κB (NF-κB), a ubiquitous transcription factor responsible for TPA-induced COX-2 expression in mouse skin. Topically applied phloretin decreased the TPA-induced DNA binding of NF-κB. In addition, phloretin inhibited the phosphorylation as well as the catalytic activity of extracellular signal-regulated kinase (ERK), which was previously found to activate NF-κB and induce COX-2 expression in TPA-treated mouse skin. Taken together, the inhibitory effects of phloretin on TPA-induced NF-κB activation and COX-2 expression through the modulation of ERK signaling may partly account for its antitumor-promoting effect on mouse skin carcinogenesis.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Jun-Wan
authors.initials: JW
authors.lastname: Shin
authors.forename: Joydeb Kumar
authors.initials: JK
authors.lastname: Kundu
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000737:chemistry / Q000378:metabolism; D005260:Female; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008812:Mice, Hairless; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010693:Phloretin / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011897:Random Allocation; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D016588:Anticarcinogenic Agents; D016328:NF-kappa B; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D010693:Phloretin