Deregulation of FOXO3A during prostate cancer progression

  • Authors:
    • Sanjeev Shukla
    • Meenakshi Shukla
    • Gregory T. MacLennan
    • Pingfu Fu
    • Sanjay Gupta
  • View Affiliations

  • Published online on: June 1, 2009     https://doi.org/10.3892/ijo_00000291
  • Pages: 1613-1620
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Abstract

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.

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June 2009
Volume 34 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Shukla S, Shukla M, MacLennan GT, Fu P and Gupta S: Deregulation of FOXO3A during prostate cancer progression. Int J Oncol 34: 1613-1620, 2009
APA
Shukla, S., Shukla, M., MacLennan, G.T., Fu, P., & Gupta, S. (2009). Deregulation of FOXO3A during prostate cancer progression. International Journal of Oncology, 34, 1613-1620. https://doi.org/10.3892/ijo_00000291
MLA
Shukla, S., Shukla, M., MacLennan, G. T., Fu, P., Gupta, S."Deregulation of FOXO3A during prostate cancer progression". International Journal of Oncology 34.6 (2009): 1613-1620.
Chicago
Shukla, S., Shukla, M., MacLennan, G. T., Fu, P., Gupta, S."Deregulation of FOXO3A during prostate cancer progression". International Journal of Oncology 34, no. 6 (2009): 1613-1620. https://doi.org/10.3892/ijo_00000291