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

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Resumo: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.
Autores principais:Goto, T.
Outros Autores:Takano, M.; Albergaria, André; Briese, J.; Pomeranz, K. M.; Cloke, B.; Fusi, L.; Feroze-Zaidi, F.; Maywald, N.; Sajin, M.
Assunto:Carcinoma, Endometrioid Cell Line, Tumor Cell Proliferation Down-Regulation Drug Resistance, Neoplasm Endometrial Neoplasms Female Forkhead Box Protein O1 Forkhead Transcription Factors Gene Expression Regulation, Neoplastic Genomic Instability Humans Endometrial cancer FOXO1 Phosphatidylinositol-3 kinase/Akt Transcription Paclitaxel GADD45alfa GADD45 alpha
Ano:2008
País:Portugal
Tipo de documento:artigo
Tipo de acesso:acesso restrito
Instituição associada:Universidade do Minho
Idioma:inglês
Origem:RepositóriUM - Universidade do Minho

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