Deregulation of FoxO3a accelerates prostate cancer progression in TRAMP mice
Article first published online: 13 JUN 2013
Copyright © 2013 Wiley Periodicals, Inc.
Volume 73, Issue 14, pages 1507–1517, October 2013
How to Cite
Shukla, S., Bhaskaran, N., MacLennan, G. T. and Gupta, S. (2013), Deregulation of FoxO3a accelerates prostate cancer progression in TRAMP mice. Prostate, 73: 1507–1517. doi: 10.1002/pros.22698
- Issue published online: 24 AUG 2013
- Article first published online: 13 JUN 2013
- Manuscript Accepted: 20 MAY 2013
- Manuscript Received: 11 APR 2013
- United States Public Health Services. Grant Numbers: RO1CA108512, RO1AT002709, RO3CA1376676
- forkhead transcription factors;
- prostate cancer;
- cell cycle
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.
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.
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.
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.