Antioxidants induce different phenotypes by a distinct modulation of signal transduction.
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.
Della Ragione
Fulvio
F
Department of Biochemistry and Biophysics, Medical School, Second University of Naples, Via Costantinopoli 16, 80138, Naples, Italy. fulvio.dellaragione@unina2.it
Cucciolla
Valeria
V
Criniti
Vittoria
V
Indaco
Stefania
S
Borriello
Adriana
A
Zappia
Vincenzo
V
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
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