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Published on: May 11, 2016
Deregulation of FoxO3a accelerates prostate cancer progression in TRAMP mice
Sanjeev Shukla1, Natarajan Bhaskaran, Gregory T Maclennan
1Department of Urology, Case Western Reserve University & The Urology Institute, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA. sanjeev.shukla@case.edu
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.
Insights
Forkhead box, class "O" (FoxO) transcription factors, particularly FoxO3a, play a crucial role in suppressing prostate cancer. Inhibiting FoxO3a accelerates tumor progression, highlighting its therapeutic potential.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Forkhead box, class "O" (FoxO) transcription factors are critical in cell signaling and possess tumor suppressor functions.
- Prostate cancer often involves PTEN loss and PI3K/Akt activation, potentially inactivating FoxO.
- This study investigates FoxO transcription factors, specifically FoxO3a, in prostate cancer progression using transgenic adenocarcinoma of the mouse prostate (TRAMP) models.
Purpose of the Study:
- To elucidate the role of FoxO transcription factors, particularly FoxO3a, in prostate cancer progression.
- To understand the regulatory mechanisms of FoxO activity in the context of PI3K/Akt signaling in prostate cancer.
- To evaluate the therapeutic potential of restoring FoxO3a activity for prostate cancer chemoprevention and treatment.
Main Methods:
- Progression of prostate cancer in TRAMP mice was monitored from 8 to 28 weeks.
- Expression, phosphorylation, and DNA binding activity of Akt and FoxO proteins (FoxO1a, FoxO3a, FoxO4) were analyzed.
- Techniques included immunoblotting, immunoprecipitation, ELISA, and immunohistochemistry.
- FoxO3a activity was inhibited using peptide treatment in TRAMP mice.
Main Results:
- Akt/PKB negatively regulates FoxO3a activity via post-translational modification in TRAMP mice.
- Increased Akt activation correlates with elevated FoxO3a phosphorylation and 14-3-3 binding, impacting transcriptional activity.
- Blocking FoxO3a activity accelerated prostate cancer progression, characterized by loss of cell cycle control and increased proliferation/survival markers.
Conclusions:
- FoxO3a activity is suppressed by Akt signaling during prostate cancer progression.
- Loss of FoxO3a function promotes tumor growth by disrupting cell cycle control and enhancing proliferation.
- Restoring FoxO3a activity is a promising therapeutic strategy for prostate cancer chemoprevention and progression inhibition.
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