Mechanism and functional consequences of loss of FOXO1 expression in endometrioid endometrial cancer cells.

Goto, T; Takano, M; Albergaria, A; Briese, J; Pomeranz, K M; Cloke, B; Fusi, L; Feroze-Zaidi, F; Maywald, N; Sajin, M; Dina, R E; Ishihara, O; Takeda, S; Lam, E W-F; Bamberger, A M; Ghaem-Maghami, S; Brosens, J J

Goto, T; Takano, M; Albergaria, A; Briese, J; Pomeranz, K M; Cloke, B; Fusi, L; Feroze-Zaidi, F; Maywald, N; Sajin, M; Dina, R E; Ishihara, O; Takeda, S; Lam, E W-F; Bamberger, A M; Ghaem-Maghami, S; Brosens, J J.

Afiliación

Goto T; 1Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London, UK.

Oncogene ; 27(1): 9-19, 2008 Jan 03.

Article en En | MEDLINE | ID: mdl-17599040

RESUMEN

The forkhead transcription factor FOXO1, a downstream target of phosphatidylinositol-3-kinase/Akt signalling pathway, regulates cyclic differentiation and apoptosis in normal endometrium, but its role in endometrial carcinogenesis is unknown. Screening of endometrial cancer cell lines demonstrated that FOXO1 is expressed in HEC-1B cells, but not in Ishikawa cells, which in turn highly express the FOXO1 targeting E3-ubiquitin ligase Skp2. FOXO1 transcript levels were also lower in Ishikawa cells and treatment with the proteasomal inhibitor was insufficient to restore expression. Lack of FOXO1 expression in Ishikawa cells was not accounted for by differential promoter methylation or activity, but correlated with increased messenger RNA (mRNA) turnover. Comparative analysis demonstrated that HEC-1B cells proliferate slower, but are more resistant to paclitaxel-mediated cell death than Ishikawa cells, which were partially reversed upon silencing of FOXO1 in HEC-1B cells or its re-expression in Ishikawa cells. We further show that FOXO1 is required for the expression of the growth arrest- and DNA-damage-inducible gene GADD45alpha. Analysis of biopsy samples demonstrated a marked loss of FOXO1 and GADD45alpha mRNA and protein expression in endometrioid endometrial cancer compared to normal endometrium. Together, these observations suggest that loss of FOXO1 perturbs endometrial homeostasis, promotes uncontrolled cell proliferation and increases susceptibility to genotoxic insults.

Asunto(s)

Carcinoma Endometrioide/metabolismo; Carcinoma Endometrioide/patología; Regulación hacia Abajo/genética; Neoplasias Endometriales/metabolismo; Neoplasias Endometriales/patología; Factores de Transcripción Forkhead/deficiencia; Factores de Transcripción Forkhead/genética; Regulación Neoplásica de la Expresión Génica/fisiología; Carcinoma Endometrioide/tratamiento farmacológico; Carcinoma Endometrioide/genética; Línea Celular Tumoral; Proliferación Celular; Regulación hacia Abajo/fisiología; Resistencia a Antineoplásicos/genética; Neoplasias Endometriales/tratamiento farmacológico; Neoplasias Endometriales/genética; Femenino; Proteína Forkhead Box O1; Factores de Transcripción Forkhead/biosíntesis; Factores de Transcripción Forkhead/fisiología; Inestabilidad Genómica/genética; Humanos

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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulación hacia Abajo / Regulación Neoplásica de la Expresión Génica / Neoplasias Endometriales / Carcinoma Endometrioide / Factores de Transcripción Forkhead Límite: Female / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2008 Tipo del documento: Article Pais de publicación: Reino Unido

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