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Deregulation of FoxO3a accelerates prostate cancer progression in TRAMP mice

Authors

  • Sanjeev Shukla,

    Corresponding author
    • Department of Urology, Case Western Reserve University & The Urology Institute, University Hospitals Case Medical Center, Cleveland, Ohio
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  • Natarajan Bhaskaran,

    1. Department of Urology, Case Western Reserve University & The Urology Institute, University Hospitals Case Medical Center, Cleveland, Ohio
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  • Gregory T. MacLennan,

    1. Department of Pathology, Case Western Reserve University, Cleveland, Ohio
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  • Sanjay Gupta

    1. Department of Urology, Case Western Reserve University & The Urology Institute, University Hospitals Case Medical Center, Cleveland, Ohio
    2. Department of Nutrition, Case Western Reserve University, Cleveland, Ohio
    3. Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, Ohio
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Correspondence to: Sanjeev Shukla, PhD, Department of Urology, Case Western Reserve University & University Hospitals Case Medical Center, 10900 Euclid Avenue, Cleveland, OH 44106. E-mail: sanjeev.shukla@case.edu

Abstract

BACKGROUND

Forkhead box, class “O” (FoxO) transcription factors are involved in multiple signaling pathways and possess tumor suppressor functions. Loss of PTEN and activation of PI3K/Akt is frequently observed in prostate cancer, which may potentially inactivate FoxO activity. We therefore investigated the role of FoxO transcription factors in prostate cancer progression, in particular FoxO3a, in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice, which mimics progressive forms of human disease.

METHODS

Prostate cancer progression in TRAMP mice was followed from 8 to 28 weeks. Expression patterns of Akt, FoxO1a, FoxO3a, FoxO4, and their phosphorylated form, DNA binding activity and downstream signaling molecules during different stages of disease progression were examined by immunoblotting, immunoprecipitation, enzyme-linked immunoabsorbant assay (ELISA), and immunohistochemistry. Inhibition of FoxO3a activity was attained by using FoxO3a peptide treatment to TRAMP mice.

RESULTS

In TRAMP mice, FoxO3a activity is negatively regulated by Akt/PKB through post-translational modification. Progressive increase in Akt activation during prostate cancer progression led to increase phosphorylation of FoxO3a and binding with 14-3-3, which potentially affected its transcriptional activity in age-specific manner. Furthermore, blocking FoxO3a activity resulted in accelerated prostate cancer progression in these mice, which was associated with the loss of cell cycle control and increased proliferation and survival markers.

CONCLUSIONS

Restoration of FoxO3a activity represents an attractive therapeutic target in the chemoprevention and possibly in inhibition of progression of prostate cancer. Prostate 73: 1507–1517, 2013. © 2013 Wiley Periodicals, Inc.

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