FoxO3a nuclear localization and its association with beta-catenin and Smads in IFN-alfa-treated hepatocellular carcinoma cell lines

CEBALLOS M P; PARODY J P; QUIROGA A D; CASELLA M; FRANCÉS D E; LAROCCA M C ; CARNOVALE C E; ALVAREZ M L; CARRILLO M C

JOURNAL OF INTERFERON AND CYTOKINE RESEARCH

MARY ANN LIEBERT INC

Lugar: New York; Año: 2014 vol. 34 p. 858 - 869

1079-9907

IFN-α2b reduces proliferation and increases apoptosis in HCC cells by decreasing β-catenin/TCF4/Smads interaction. FoxO3a participates in proliferation and apoptosis and interacts with β-catenin and Smads. FoxO3a is inhibited by Akt, IKKb and Erk which promote FoxO3a sequestration in the cytosol and accumulates in the nucleus upon phosphorylation by JNK and p38MAPK. We analyzed FoxO3a subcellular localization, the participating kinases, FoxO3a/b-catenin/Smads association, and FoxO3a target genes expression in IFN-α2b-stimulated HepG2/C3A and Huh7 cells. Total FoxO3a and Akt-phosphorylated FoxO3a levels decreased in the cytosol, whereas total FoxO3a levels increased in the nucleus upon IFN-α2b stimulus. IFN-α2b reduced Akt, IKKb and Erk activation, and increased JNK and p38MAPK activation. p38MAPK inhibition blocked IFN-α2b-induced FoxO3a nuclear localization. IFN-α2b enhanced FoxO3a association with b-catenin and Smad2/3/7. Two-step co-immunoprecipitation experiments suggest that these proteins co-exist in the same complex. The expression of several FoxO3a target genes increased with IFN-α2b. FoxO3a knock down prevented the induction of these genes, suggesting that FoxO3a acts as mediator of IFN-α2b action. Results suggest a β-catenin/Smads switch from TCF4 to FoxO3a. Such events would contribute to the IFN-α2b-mediated effects on the cellular fate. These results demonstrate new mechanisms for IFN-α action, showing the importance of its application in antitumorigenic therapies.