title: Survival signaling elicited by 27-hydroxycholesterol through the combined modulation of cellular redox state and ERK/Akt phosphorylation.
abstract: The oxysterol 27-hydroxycholesterol (27-OH) is increasingly considered to be involved in a variety of pathophysiological processes, having been shown to modulate cell proliferation and metabolism, and also to exert proinflammatory and proapoptotic effects. This study aimed to elucidate the molecular pathways whereby 27-OH may generate survival signals in cells of the macrophage lineage, and to clarify whether its known prooxidant effect is involved in that process. A net up-regulation of survival signaling, involving the extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/Akt phosphorylation pathways, was observed in U937 promonocytic cells cultivated over time in the presence of a low micromolar concentration of the oxysterol. Interestingly, the up-regulation of both kinases was shown to be closely dependent on an early 27-OH-induced intracellular increase of reactive oxygen species (ROS). In turn, stimulation of ERK and PI3K/Akt both significantly quenched ROS steady state and markedly phosphorylated Bad, thereby determining a marked delay of the oxysterol׳s proapoptotic action. The 27-OH-induced survival pathways thus appear to be redox modulated and, if they occur within or nearby inflammatory cells during progression of chronic diseases such as cancer and atherosclerosis, they could significantly impact the growth and evolution of such diseases.
authors.affiliation: Biological Sciences and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Orhanli-Tuzla, 34956 Istanbul, Turkey. Electronic address: beyzav@sabanciuniv.edu.
authors.forename: Beyza
authors.initials: B
authors.lastname: Vurusaner
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy. Electronic address: paola.gamba@unito.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Gamba
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy. Electronic address: gabriella.testa@unito.it.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Testa
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy. Electronic address: simona.gargiulo@unito.it.
authors.forename: Simona
authors.initials: S
authors.lastname: Gargiulo
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy. Electronic address: fiorella.biasi@unito.it.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Biasi
authors.affiliation: Department of Medical-Surgical Sciences and Biotechnology, Vascular Biology and Mass Spectrometry Laboratory, Sapienza University of Rome, Latina, Italy. Electronic address: chiara.zerbinati@uniroma1.it.
authors.forename: Chiara
authors.initials: C
authors.lastname: Zerbinati
authors.affiliation: Department of Medical-Surgical Sciences and Biotechnology, Vascular Biology and Mass Spectrometry Laboratory, Sapienza University of Rome, Latina, Italy. Electronic address: luigi.iuliano@uniroma1.it.
authors.forename: Luigi
authors.initials: L
authors.lastname: Iuliano
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy. Electronic address: gabriella.leonarduzzi@unito.it.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Leonarduzzi
authors.affiliation: Biological Sciences and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Orhanli-Tuzla, 34956 Istanbul, Turkey. Electronic address: huveyda@sabanciuniv.edu.
authors.forename: Huveyda
authors.initials: H
authors.lastname: Basaga
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy. Electronic address: giuseppe.poli@unito.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Poli
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D006888:Hydroxycholesterols; D017382:Reactive Oxygen Species; C076996:27-hydroxycholesterol; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Oxysterols; ROS; Survival signaling