title: Apoptosis induced by oxidized lipids is associated with up-regulation of p66Shc in intestinal Caco-2 cells: protective effects of phenolic compounds.
abstract: In this study, we investigated the alterations of the redox balance induced by the lipid fraction of oxLDL in Caco-2 intestinal cells, and the effects of tyrosol and protocatechuic acid, two dietary phenolic compounds. We found that oxidized lipids extracted from oxLDL (LipE) induced oxidative stress by determining, 6 h after treatment, ROS overproduction (about a 100% and a 43% increase of O*2 and H2O2 production, respectively, P<.05: LipE vs. control) and, 12 h after treatment, GSH depletion (about a 26% decrease, P<.05: LipE vs. control), and by impairing the activities of superoxide dismutase, catalase and glutathione peroxidase. In response to the induced oxidative stress, we observed significant overexpression of glutathione peroxidase (6 h after treatment: P<.05), glutathione reductase and gamma-glutamylcysteine synthetase (12 h after treatment: P<.05). Notably, when GSH depletion occurred, p66Shc protein expression increased by about 300% with respect to control (P<.001; LipE vs. control). These effects were fully counteracted by dietary phenolics which inhibited ROS overproduction and GSH consumption, rendered the reactive transcription of glutathione-associated enzymes unnecessary and blocked the intracellular signals leading to the overexpression and rearrangement of p66Shc signalling molecule. Altogether, these results suggest that the impairment of the antioxidant system hijacks intestinal cells towards an apoptotic-prone phenotype via the activation of p66Shc molecule. They also propose a reappraisal of dietary polyphenols as intestinal protecting agents, indicating the antiapoptotic effect as a further mechanism of action of these antioxidant compounds.
authors.affiliation: National Centre for Food Quality and Risk Assessment, Istituto Superiore di Sanità, 299-00161 Rome, Italy. clagiovn@iss.it
authors.forename: Claudio
authors.initials: C
authors.lastname: Giovannini
authors.forename: Beatrice
authors.initials: B
authors.lastname: Scazzocchio
authors.forename: Paola
authors.initials: P
authors.lastname: Matarrese
authors.forename: Rosaria
authors.initials: R
authors.lastname: Varì
authors.forename: Massimo
authors.initials: M
authors.lastname: D'Archivio
authors.forename: Roberta
authors.initials: R
authors.lastname: Di Benedetto
authors.forename: Stefania
authors.initials: S
authors.lastname: Casciani
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Dessì
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Straface
authors.forename: Walter
authors.initials: W
authors.lastname: Malorni
authors.forename: Roberta
authors.initials: R
authors.lastname: Masella
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D018938:Caco-2 Cells; D002374:Catalase / Q000378:metabolism; D017931:DNA Primers; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006801:Humans; D007422:Intestines / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010636:Phenols / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013482:Superoxide Dismutase / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; D008077:Lipoproteins, LDL; D010636:Phenols; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C099252:oxidized low density lipoprotein; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005980:Glutathione Reductase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione