title: FoxO3a modulation and promotion of apoptosis by interferon-α2b in rat preneoplastic liver.
abstract: BACKGROUND
  FoxO3a, a member of the FOXO family of transcription factors, is expressed in adult liver and modulates the expression of genes involved in apoptosis. FoxO3a is post-translationally regulated, negatively by PI3K/Akt and MAPK/Erk and positively by oxidative stress/JNK pathways. In previous works, we have demonstrated that interferon-α2b (IFN-α2b) induces apoptosis of hepatic preneoplastic foci through the production of reactive oxygen species (ROS).
  
  
  OBJECTIVE
  To investigate the post-translational signal events triggered by the oxidative stress induced by IFN-α2b and the modulation of FoxO3a transcriptional activity during these events in rat preneoplastic liver.
  
  
  METHODS
  Adult male Wistar rats were subjected to a two-phase model of hepatocarcinogenesis. A group of animals received IFN-α2b and another group received IFN-α2b and ascorbic acid (ASC), by intraperitoneal injection. Lipid peroxidation, immunohistochemistry, immunoblotting, co-immunoprecipitation and sqRT-PCR assays were performed to explore the role of ROS, JNK, Akt, Erk, FoxO3a, β-catenin and PUMA in the IFN-α2b-mediated apoptotic mechanism.
  
  
  RESULTS
  In vivo IFN-α2b treatment induced endogenous production of ROS which activated JNK. IFN-α2b blocked the activation of Akt and Erk, avoiding FoxO3a activity repression. Activated JNK was responsible for the nuclear translocation and transcriptional activity of FoxO3a which positively modulated the expression of PUMA, a proapoptotic player. In addition, nuclear FoxO3a competed for the nuclear β-catenin associated to TCF, inhibiting the canonical Wnt signalling pathway.
  
  
  CONCLUSIONS
  The data presented here propose a model in which in vivo IFN-α2b treatment induces nuclear translocation and transcriptional activity of FoxO3a, triggering the mitochondrial apoptotic pathway in hepatic preneoplastic foci.
authors.affiliation: Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Rosario, Argentina.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Parody
authors.forename: Maria P
authors.initials: MP
authors.lastname: Ceballos
authors.forename: Ariel D
authors.initials: AD
authors.lastname: Quiroga
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Frances
authors.forename: Cristina E
authors.initials: CE
authors.lastname: Carnovale
authors.forename: Gerardo B
authors.initials: GB
authors.lastname: Pisani
authors.forename: Maria L
authors.initials: ML
authors.lastname: Alvarez
authors.forename: Maria C
authors.initials: MC
authors.lastname: Carrillo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D063646:Carcinogenesis / Q000187:drug effects*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D018384:Oxidative Stress / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins
keywords: MAPK; PUMA; hepatocarcinogenesis; oxidative stress; rats