Activation of the human androgen receptor through a protein kinase A signaling pathway.
Open accessAbstract
Aberrant activation of the androgen receptor through signaling pathways independent of androgen may be responsible for the progression of prostate tumors to the rapidly proliferating androgen-independent state. In this study, the effects of protein kinase A modulators on human androgen receptor activity were tested. Using an adenoviral DNA delivery system, we demonstrate that the androgen receptor can be activated by a protein kinase A activator, forskolin, in the absence of androgen when androgen receptor is co-transfected into monkey kidney CV1 cells or human prostate PC-3 cells with androgen-responsive reporters. Immunoblotting reveals that there is no significant change in androgen receptor protein level following forskolin treatment, suggesting that the enhanced activity is due to activation of the receptor. This activation can be blocked by a protein kinase A inhibitor peptide. Two potent anti-androgens, casodex and flutamide, can significantly reduce this activation, confirming that the ligand-independent pathway is an androgen receptor-mediated phenomenon. An intact DNA binding domain of the receptor is critical for this alternate signaling pathway since mutants with reduced DNA binding ability are inactive. The phosphorylation status of the androgen receptor or associated proteins may critically modulate receptor activity and should be considered when designing improved approaches to prostate cancer therapy.
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When prostate cancer cells are treated with forskolin, AR-driven transcription is increased from AR-responsive promoters, an effect quenched by the addition of AR antagonists bicalutamide and flutamide.
“When prostate cancer cells are treated with the inhibitor forskolin (a naturally derived molecule that activates adenylyl cyclase, thus increasing the intracellular levels of cAMP and consequently protein kinase A), AR-driven transcription is increased from ARresponsive promoters, an effect that is quenched by the addition of AR antagonists bicalutamide and flutamide (55,56).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [55]
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- Authors
- Nazareth, L. V., & Weigel, N. L.
- Affiliations
- Baylor College of Medicine (US)
- Corresponding author
- Weigel, Nancy L.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1996-08
- Volume
- 271
- Issue
- 33
- Pages
- 19900-19907
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1988679331
- Cited by
- 429
- References
- 40
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 1 · 2022: 6 · 2021: 2 · 2020: 4 · 2019: 2 · 2018: 6 · 2017: 5 · 2016: 6 · 2015: 7 · 2014: 6 · 2013: 16 · 2012: 14
- FWCI
- 22.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (CA58204)
- National Cancer Institute (CA-58204, P50CA058204)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Keywords
- androgen receptor, protein kinase A signaling, forskolin, ligand-independent receptor activation, prostate cancer, castration-resistant prostate cancer, androgen receptor antagonists, bicalutamide, flutamide, DNA-binding domain, receptor phosphorylation, adenoviral gene transfer, PC-3 cells
- MeSH terms
- Androgen Antagonists, Androgens, Anilides, Animals, Cell Line, Cell Nucleus, Chlorocebus aethiops, DNA-Binding Proteins, Enzyme Inhibitors, Flutamide, Colforsin, Gene Expression Regulation, Humans, Male, Nitriles, Receptors, Androgen, Receptors, Progesterone, Structure-Activity Relationship, Tosyl Compounds, Transcription, Genetic, Signal Transduction, Cyclic AMP-Dependent Protein Kinases, Androgen Receptor Antagonists
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