Deregulation of FOXO3A during prostate cancer progression.
Forkhead box transcription factor FOXO3A, an important regulator of cellular function, is thought to act as a tumor suppressor. We studied whether alterations in FOXO3A activity occur in prostate tumorigenesis. Our studies demonstrate that FOXO3A activity is negatively regulated by Akt/PKB through posttranslational modifications. In prostate cancer cells, Akt activation causes increased accumulation of FOXO3A and its binding chaperone protein 14-3-3 in the cytosol. Higher levels of FOXO3A in the cytosol correlated with phosphorylation at Ser253, which accounted for its nuclear exclusion. Dominant negative Akt approach in PC-3 cells increased FOXO3A accumulation in the nucleus, causing upregulation of the downstream target, MnSOD. Conversely, stable DU145-Akt over-expressing cells exhibited decreased FOXO3A levels in the nucleus. Similar findings were noted in prostate tumor specimens, in which marked cytoplasmic accumulation of FOXO3A and 14-3-3 in prostate tumors was observed with increasing Gleason grade, in contrast to exclusively nuclear accumulation in benign prostate cells. These findings correlate with decreased FOXO3A DNA binding activity along with down-modulation of FOXO3A transcriptional activity with increasing tumor grade. Our findings demonstrate that tumor associated alterations and redistribution of FOXO3A are frequent events in the etiology of prostate cancer.
Department of Urology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
Sanjeev
S
Shukla
Meenakshi
M
Shukla
Gregory T
GT
Maclennan
Pingfu
P
Fu
Sanjay
S
Gupta
D048948:14-3-3 Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011470:Prostatic Hyperplasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D048948:14-3-3 Proteins; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D013482:Superoxide Dismutase; D014157:Transcription Factors; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; C108803:FOXO4 protein, human