FoxO3a modulation and promotion of apoptosis by interferon-alfa2b in rat preneoplastic liver

JUAN P. PARODY; MARIA P. CEBALLOS; ARIEL D. QUIROGA; DANIEL ELEAZAR FRANCÉS; CRISTINA E. CARNOVALE; GERARDO B. PISANI; MARIA L. ALVAREZ; MARIA C. CARRILLO

LIVER INTERNATIONAL

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2014 vol. 34 p. 1566 - 1577

1478-3223

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-alfa2b (IFN-alfa2b) 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-alfa2b 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-alfa2b and another group received IFN-alfa2b 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, beta-catenin and PUMA in the IFN-alfa2b-mediated apoptotic mechanism.RESULTS: In vivo IFN-alfa2b treatment induced endogenous production of ROS which activated JNK. IFN-alfa2b 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 beta-catenin associated to TCF, inhibiting the canonical Wnt signaling pathway.CONCLUSIONS: The data presented here propose a model in which in vivo IFN-alfa2b treatment induces nuclear translocation and transcriptional activity of FoxO3a, triggering the mitochondrial apoptotic pathway in hepatic preneoplastic foci.