gingerol and Cell-Transformation--Neoplastic

A wide variety of phenolic substances derived from spice possess potent antimutagenic and anticarcinogenic activities. Examples are curcumin, a yellow colouring agent, contained in turmeric (Curcuma longa L., Zingiberaceae), [6]-gingerol, a pungent ingredient present in ginger (Zingiber officinale Roscoe, Zingiberaceae) and capsaicin, a principal pungent principle of hot chili pepper (Capsicum annuum L, Solanaceae). The chemopreventive effects exerted by these phytochemicals are often associated with their antioxidative and anti-inflammatory activities. Cyclo-oxygenase-2 (COX-2) has been recognized as a molecular target of many chemopreventive as well as anti-inflammatory agents. Recent studies have shown that COX-2 is regulated by the eukaryotic transcription factor NF-kappaB. This short review summarizes the molecular mechanisms underlying chemopreventive effects of the aforementioned spice ingredients in terms of their effects on intracellular signaling cascades, particularly those involving NF-kappaB and mitogen-activated protein kinases.

Topics: Animals; Anti-Inflammatory Agents; Anticarcinogenic Agents; Antimutagenic Agents; Antioxidants; Capsaicin; Catechols; Cell Transformation, Neoplastic; Curcumin; Cyclooxygenase 2; Fatty Alcohols; Humans; Isoenzymes; Membrane Proteins; Mutagens; NF-kappa B; Prostaglandin-Endoperoxide Synthases; Spices

Recent data indicate that transforming growth factor-beta1 (TGF-beta1) can act to promote tumour progression in the late stages of carcinogenesis. The mechanism by which this occurs is unknown although a ligand-induced epithelial-mesenchymal transition (EMT) is thought to be important. In this study, we demonstrate that active Ras is required for TGF-beta1-induced EMT in human keratinocytes and that epidermal growth factor (EGF) can substitute for mutant Ras. EMT was reversed by the removal of TGF-beta1. Under conditions of TGF-beta1-induced EMT, cells were growth inhibited by the ligand resulting in G1 arrest. In cells containing normal Ras, TGF-beta1-activated ERK and p38 mitogen-activated protein kinases (MAPKs), and levels of activation were further increased by co-treatment with EGF. Inhibition of MAPK pathways and Smad2/3 signalling blocked the induction of EMT by TGF-beta1. Further, inhibition of the AP-1 transcriptional complex by [6]-Gingerol, or by the ectopic expression of JDP2, blocked TGF-beta1-induced EMT and conversely, stimulation of AP-1 by 12-O-tetradecanoylphorbol 13-acetate (TPA) substituted for EGF in the induction of EMT by TGF-beta1 in cells containing normal Ras. The presence of oncogenic Ras, the treatment of cells with EGF, or the treatment of cells with TPA to activate AP-1, potentiated TGF-beta1-induced Smad-dependent transcription, an effect that was attenuated by the inhibition of MAPKs and AP-1. The results demonstrate that active Ras and TGF-beta1 co-operate to reversibly induce EMT in human keratinocytes by mechanisms that involve MAPKs, Smad2/3 and AP-1. Further we demonstrate that MAPK/AP-1 signalling enhances Smad transcriptional activity under conditions associated with TGF-beta1-induced EMT.

Topics: Blotting, Western; Catechols; Cell Cycle; Cell Proliferation; Cell Transformation, Neoplastic; DNA-Binding Proteins; Epithelial Cells; Fatty Alcohols; Genes, ras; Humans; Keratinocytes; Luciferases; Mesoderm; Mutagens; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Plasmids; Signal Transduction; Skin Neoplasms; Smad3 Protein; Trans-Activators; Transcription Factor AP-1; Transforming Growth Factor beta; Transforming Growth Factor beta1; Zingiber officinale

Many spices, including plants of the ginger family, possess anticarcinogenic activity. However, the molecular mechanisms by which they exert their antitumorigenic effects are unknown. Activator protein 1 (AP-1) has a critical role in tumor promotion, and blocking of tumor promoter-induced activation of AP-1 inhibits neoplastic transformation. Epidermal growth factor induces cell transformation and AP-1 activity. The purpose of this study was to investigate the effect of two structurally related compounds of the ginger family, [6]-gingerol and [6]-paradol, on EGF-induced cell transformation and AP-1 activation. Our results provide the first evidence that both block EGF-induced cell transformation but act by different mechanisms.

Topics: Animals; Anticarcinogenic Agents; Catechols; Cell Death; Cell Line; Cell Transformation, Neoplastic; DNA; Enzyme Induction; Epidermal Cells; Epidermal Growth Factor; Epidermis; Fatty Alcohols; Guaiacol; Ketones; Mice; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Plants, Medicinal; Transcription Factor AP-1