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FoxO3a modulation and promotion of apoptosis by interferon‐α2b in rat preneoplastic liver
Author(s) -
Parody Juan P.,
Ceballos Maria P.,
Quiroga Ariel D.,
Frances Daniel E.,
Carnovale Cristina E.,
Pisani Gerardo B.,
Alvarez Maria L.,
Carrillo Maria C.
Publication year - 2014
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.12421
Subject(s) - protein kinase b , mapk/erk pathway , apoptosis , oxidative stress , wnt signaling pathway , signal transduction , chemistry , reactive oxygen species , pi3k/akt/mtor pathway , cancer research , microbiology and biotechnology , biology , biochemistry
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 PI 3K/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 ). Aims 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 sq RT ‐ 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.