Abstract:
: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.
journal_name
Oncogenejournal_title
Oncogeneauthors
Goto T,Takano M,Albergaria A,Briese J,Pomeranz KM,Cloke B,Fusi L,Feroze-Zaidi F,Maywald N,Sajin M,Dina RE,Ishihara O,Takeda S,Lam EW,Bamberger AM,Ghaem-Maghami S,Brosens JJdoi
10.1038/sj.onc.1210626subject
Has Abstractpub_date
2008-01-03 00:00:00pages
9-19issue
1eissn
0950-9232issn
1476-5594pii
1210626journal_volume
27pub_type
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