FoxO3a Nuclear Localization and Its Association with beta-Catenin and Smads in IFN-alpha-Treated Hepatocellular Carcinoma Cell Lines

MARÍA PAULA CEBALLOS; JUAN PABLO PARODY; ARIEL DARÍO QUIROGA; MARÍA LAURA CASELLA; DANIEL ELEAZAR FRANCÉS; MARÍA CECILIA LAROCCA; CRISTINA ESTER CARNOVALE; MARÍA DE LUJÁN ALVAREZ; MARÍA CRISTINA CARRILLO

JOURNAL OF INTERFERON AND CYTOKINE RESEARCH

MARY ANN LIEBERT INC

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

1079-9907

Interferon-alpha2b (IFN-alpha2b) reduces proliferation and increases apoptosis in hepatocellular carcinoma cells by decreasing beta-catenin/TCF4/Smads interaction. Forkhead box O-class 3a (FoxO3a) participates in proliferation and apoptosis and interacts with beta-catenin and Smads. FoxO3a is inhibited by Akt, IκB kinase beta (IKKbeta), and extracellular-signal-regulated kinase (Erk), which promote FoxO3a sequestration in the cytosol, and accumulates in the nucleus upon phosphorylation by c-Jun N-terminal kinase (JNK) and p38 mitogen-activated kinase (p38 MAPK). We analyzed FoxO3a subcellular localization, the participating kinases, FoxO3a/beta-catenin/Smads association, and FoxO3a target gene expression in IFN-alpha2b-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-alpha2b stimulus. IFN-alpha2b reduced Akt, IKKbeta, and Erk activation, and increased JNK and p38 MAPK activation. p38 MAPK inhibition blocked IFN-alpha2b-induced FoxO3a nuclear localization. IFN-alpha2b enhanced FoxO3a association with beta-catenin and Smad2/3/7. Two-step coimmunoprecipitation experiments suggest that these proteins coexist in the same complex. The expression of several FoxO3a target genes increased with IFN-alpha2b. FoxO3a knockdown prevented the induction of these genes, suggesting that FoxO3a acts as mediator of IFN-alpha2b action. Results suggest a beta-catenin/Smads switch from TCF4 to FoxO3a. Such events would contribute to the IFN-alpha2b-mediated effects on cellular proliferation and apoptosis. These results demonstrate new mechanisms for IFN-alpha action, showing the importance of its application in antitumorigenic therapies. Afrikaans Albanian Arabic Armenian Azerbaijani Basque Belarusian Bulgarian Catalan Chinese (Simplified) Chinese (Traditional) Croatian Czech Danish Detect language Dutch English Estonian Filipino Finnish French Galician Georgian German Greek Haitian Creole Hebrew Hindi Hungarian Icelandic Indonesian Irish Italian Japanese Korean Latin Latvian Lithuanian Macedonian Malay Maltese Norwegian Persian Polish Portuguese Romanian Russian Serbian Slovak Slovenian Spanish Swahili Swedish Thai Turkish Ukrainian Urdu Vietnamese Welsh Yiddish⇄ Afrikaans Albanian Arabic Armenian Azerbaijani Basque Belarusian Bulgarian Catalan Chinese (Simplified) Chinese (Traditional) Croatian Czech Danish Dutch English Estonian Filipino Finnish French Galician Georgian German Greek Haitian Creole Hebrew Hindi Hungarian Icelandic Indonesian Irish Italian Japanese Korean Latin Latvian Lithuanian Macedonian Malay Maltese Norwegian Persian Polish Portuguese Romanian Russian Serbian Slovak Slovenian Spanish Swahili Swedish Thai Turkish Ukrainian Urdu Vietnamese Welsh Yiddish Detect language » Hungarian