title: Antioxidants induce different phenotypes by a distinct modulation of signal transduction.
abstract: Antioxidants are known to exert a preventive activity against degenerative diseases. Here, we investigated the mechanism of action of three antioxidants: resveratrol, which causes differentiation of HL-60 cells, and hydroxytyrosol and pyrrolidine dithiocarbamate which, in the same model system, activate apoptosis. The expression profile of hydroxytyrosol-treated cells showed the up-regulation of several genes, including c-jun and egr1. Pyrrolidine dithiocarbamate activates both genes, while resveratrol increases uniquely egr1. A selective modulation of signalling pathway explained this finding. All antioxidants up-regulate Erk1/2, while only hydroxytyrosol and pyrrolidine dithiocarbamate activate c-Jun N-terminal kinase (JNK). Since JNK induces apoptosis by Bcl-2 phosphorylation, we investigated this event. Bcl-2 phosphorylation was increased by hydroxytyrosol and pyrrolidine dithiocarbamate and not by resveratrol. Our results indicate that the different phenotypical effects of antioxidants correlate with modulation of selective transduction pathways.
authors.affiliation: Department of Biochemistry and Biophysics, Medical School, Second University of Naples, Via Costantinopoli 16, 80138, Naples, Italy. fulvio.dellaragione@unina2.it
authors.forename: Fulvio
authors.initials: F
authors.lastname: Della Ragione
authors.forename: Valeria
authors.initials: V
authors.lastname: Cucciolla
authors.forename: Vittoria
authors.initials: V
authors.lastname: Criniti
authors.forename: Stefania
authors.initials: S
authors.lastname: Indaco
authors.forename: Adriana
authors.initials: A
authors.lastname: Borriello
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Zappia
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D051766:Early Growth Response Protein 1; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D017874:Immediate-Early Proteins; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008956:Models, Chemical; D010641:Phenotype; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology*; D013859:Thiocarbamates / Q000494:pharmacology*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D017874:Immediate-Early Proteins; D016755:Proto-Oncogene Proteins c-jun; D011725:Pyridines; D011759:Pyrrolidines; D013267:Stilbenes; D013859:Thiocarbamates; D014157:Transcription Factors; C005975:3,4-dihydroxyphenylethanol; C020972:pyrrolidine dithiocarbamic acid; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D010626:Phenylethyl Alcohol; C093642:SB 203580; D000077185:Resveratrol; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one