title: FOXO3 is inhibited by oncogenic PI3K/Akt signaling but can be reactivated by the NSAID sulindac sulfide.
abstract: BACKGROUND
  Overactivation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway has emerged as a pivotal trigger of thyroid carcinogenesis. Recent findings from other tumor entities revealed that PI3K/Akt-driven carcinogenesis critically involves the inactivation of the tumor-suppressive transcription factor Forkhead box O (FOXO)-3. However, little is known about FOXO3 in the thyroid context.
  
  
  OBJECTIVE
  We sought to investigate the influence of the thyroid oncogenes BRAFV600E, H-RASV12, and p110α (H1074R) on the regulation of the PI3K downstream target FOXO3 in vitro. Furthermore, the impact of the expression of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) on the transcriptional activity of FOXO3 was assessed in a panel of 44 human thyroid tumors. Finally, we tried to modulate FOXO3 activity pharmacologically with help of the nonsteroidal antiinflammatory drug sulindac sulfide (SS).
  
  
  RESULTS
  We found that the overexpression of p110α H1074R results in the inactivation of FOXO3 via its nuclear exclusion. In vivo, we observed a direct correlation between PTEN expression and the transcriptional activation of FOXO3. In vitro, we found that stimulation with SS reversed PI3K/Akt-driven inactivation of FOXO3, resulting in its nuclear relocation and a combined induction of the antiproliferative FOXO target genes Gadd45α and p27(kip1) and the proapoptotic FOXO target gene Bim in benign (FRTL-5) and malignant human thyrocytes (FTC-133). In agreement with this, SS promoted the cell cycle arrest and apoptosis in thyroid cells, which could be amplified by the transfection of exogenous FOXO3.
  
  
  CONCLUSIONS
  Our data suggest that deregulation of proapoptotic FOXO3 represents a central step in PI3K/Akt-mediated thyroid carcinogenesis. Thus, SS might represent an attractive pharmacological tool for targeting thyroid neoplasia with aberrant PI3K/Akt/FOXO3 signaling.
authors.affiliation: Clinic of Endocrinology, Department of Medicine, University Hospital Essen, Hufelandstr 55, D-45147 Essen, Germany.
authors.forename: Carl
authors.initials: C
authors.lastname: Weidinger
authors.forename: Kerstin
authors.initials: K
authors.lastname: Krause
authors.forename: Kathrin
authors.initials: K
authors.lastname: Mueller
authors.forename: Antje
authors.initials: A
authors.lastname: Klagge
authors.forename: Dagmar
authors.initials: D
authors.lastname: Fuhrer
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002277:Carcinoma / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D009857:Oncogenes / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D013467:Sulindac; C499515:FOXO3 protein, rat; C025462:sulindac sulfide