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Antagonistic Functions of Androgen Receptor and NF-κB in Prostate Cancer-Experimental and Computational Analyses
José Basílio1,2, Bernhard Hochreiter1, Bastian Hoesel1
1Center for Physiology and Pharmacology, Institute of Vascular Biology and Thrombosis Research, Medical University Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria.
Abstract:
Prostate cancer is very frequent and is, in many countries, the third-leading cause of cancer related death in men. While early diagnosis and treatment by surgical removal is often curative, metastasizing prostate cancer has a very bad prognosis. Based on the androgen-dependence of prostate epithelial cells, the standard treatment is blockade of the androgen receptor (AR). However, nearly all patients suffer from a tumor relapse as the metastasizing cells become AR-independent. In our study we show a counter-regulatory link between AR and NF-κB both in human cells and in mouse models of prostate cancer, implying that inhibition of AR signaling results in induction of NF-κB-dependent inflammatory pathways, which may even foster the survival of metastasizing cells. This could be shown by reporter gene assays, DNA-binding measurements, and immune-fluorescence microscopy, and furthermore by a whole set of computational methods using a variety of datasets. Interestingly, loss of PTEN, a frequent genetic alteration in prostate cancer, also causes an upregulation of NF-κB and inflammatory activity. Finally, we present a mathematical model of a dynamic network between AR, NF-κB/IκB, PI3K/PTEN, and the oncogene c-Myc, which indicates that AR blockade may upregulate c-Myc together with NF-κB, and that combined anti-AR/anti-NF-κB and anti-PI3K treatment might be beneficial.
Insights
Androgen receptor (AR) blockade in prostate cancer can paradoxically increase inflammation via NF-κB signaling, potentially aiding tumor survival. Combined therapies targeting AR and NF-κB may offer improved treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Systems Biology
Background:
- Prostate cancer is a leading cause of cancer death in men, with metastatic disease having a poor prognosis.
- Standard treatment involves androgen receptor (AR) blockade, but resistance and relapse are common as tumors become AR-independent.
- AR signaling is crucial for prostate epithelial cell function, and its blockade is a primary therapeutic strategy.
Purpose of the Study:
- To investigate the relationship between androgen receptor (AR) signaling and NF-κB inflammatory pathways in prostate cancer.
- To explore the role of PTEN loss in NF-κB activation and inflammation in prostate cancer.
- To develop a mathematical model of the AR-NF-κB network to identify potential therapeutic strategies.
Main Methods:
- Reporter gene assays, DNA-binding measurements, and immunofluorescence microscopy were used to study AR and NF-κB interactions.
- Computational methods and analysis of diverse datasets were employed to understand pathway dynamics.
- A mathematical model was constructed to simulate the network involving AR, NF-κB/IκB, PI3K/PTEN, and c-Myc.
Main Results:
- A counter-regulatory link was identified between AR and NF-κB in human prostate cancer cells and mouse models.
- Inhibition of AR signaling led to the induction of NF-κB-dependent inflammatory pathways, potentially promoting survival of metastatic cells.
- Loss of PTEN, a common genetic alteration, was associated with increased NF-κB activity and inflammation.
Conclusions:
- AR blockade in prostate cancer can induce compensatory NF-κB activation and inflammation, contributing to treatment resistance.
- Combined blockade of AR, NF-κB, and PI3K pathways may represent a more effective therapeutic approach for advanced prostate cancer.
- Understanding these complex network interactions is crucial for developing novel treatment strategies against refractory prostate cancer.
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