title: Resveratrol modulates phorbol ester-induced pro-inflammatory signal transduction pathways in mouse skin in vivo: NF-kappaB and AP-1 as prime targets.
abstract: Functional abnormalities of intracellular signaling network cause the disruption in homeostasis maintained by critical cellular components, thereby accelerating premalignant and malignant transformation. Multiple lines of evidence suggest that an elevated expression of cyclooxygenase-2 (COX-2) is causally linked to tumorigenesis. The exposure to oxidative/pro-inflammatory stimuli turns on signaling arrays mediated by diverse classes of kinases and transcription factors, which may lead to aberrant expression of COX-2. We have attempted to unravel the signal transduction pathways involved in elevated COX-2 expression in mouse skin stimulated with a prototype tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and its modulation by resveratrol, a phytoalexin known to exert potential chemopreventive effects. Our study revealed that topical application of TPA induced COX-2 expression in mouse skin via activation of nuclear factor-kappaB (NF-kappaB), which is regulated by upstream IkappaB kinase (IKK) or differentially by mitogen-activated protein (MAP) kinases. Besides NF-kappaB, the p38 MAP kinase-mediated activation of activator protein-1 (AP-1) has also been attributed to TPA-induced COX-2 expression in mouse skin. Among the MAP kinases, extracellular signal-regulated protein kinase (ERK) and p38 MAP kinase have been shown to regulate TPA-induced NF-kappaB activation, while p38 MAP kinase and c-Jun-N-terminal kinase are preferentially involved in TPA-induced activation of AP-1 in mouse skin in vivo. This commentary focuses on resveratrol modulation of intracellular signaling pathways involved in aberrant COX-2 expression in TPA-stimulated mouse skin to delineate molecular mechanisms underlying antitumor promoting effects of resveratrol.
authors.affiliation: National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Shinlim-9-dong, Kwanak-gu, Seoul 151-742, South Korea.
authors.forename: Joydeb Kumar
authors.initials: JK
authors.lastname: Kundu
authors.forename: Young Kee
authors.initials: YK
authors.lastname: Shin
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004359:Drug Therapy, Combination; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects*; D012867:Skin / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D013267:Stilbenes / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D052246:Cyclooxygenase 2 Inhibitors; D016328:NF-kappa B; D013267:Stilbenes; D018808:Transcription Factor AP-1; D051546:Cyclooxygenase 2; D013755:Tetradecanoylphorbol Acetate; D000077185:Resveratrol