Ligand-independent activation of androgen receptors by Rho GTPase signaling in prostate cancer.
Open accessAbstract
Prostate cancer invariably recurs after androgen deprivation therapy. Growth of this recurrent/androgen-independent form of prostate cancer may be due to increased androgen receptor (AR) transcriptional activity in the absence of androgen. This ligand-independent AR activation is promoted by some growth factors but the mechanism is not well understood. Vav3, a Rho guanosine triphosphatase guanine nucleotide exchange factor, which is activated by growth factors, is up-regulated in human prostate cancer. We show here that Vav3 levels increase during in vivo progression of prostate cancer to androgen independence. Vav3 strikingly enhanced growth factor activation of AR in the absence of androgen. Because Vav3 may be chronically activated in prostate cancer by growth factor receptors, we examined the effects of a constitutively active (Ca) form of Vav3 on AR transcriptional activity. Ca Vav3 caused nuclear localization and ligand-independent activation of AR via the Rho guanosine triphosphatase, Rac1. Ca Rac1 activation of AR occurred, in part, through MAPK/ERK signaling. Expression of active Rac1 conferred androgen-independent growth of prostate cancer cells in culture, soft agar, and mice. These findings suggest that Vav3/Rac 1 signaling is an important modulator of ligand-independent AR transcriptional activity in prostate cancer progression.
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Vav3 signaling induces nuclear localization of the AR via activation of Rho guanosine triphosphatase Rac1, whose downstream signaling includes members of the MAPK pathway, including ERK.
“This signaling pathway induces nuclear localization of the AR via the activation Rho guanosine triphosphatase Rac1, whose downstream signaling includes members of the MAPK pathway, including ERK (46).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [46]
The expression of Vav3, a Rho guanosine triphosphate guanine nucleotide exchange factor, is upregulated in prostate cancer and has been demonstrated to enhance EGF/IGF activation of the AR in the absence of androgen.
“The expression of Vav3, a Rho guanos-ine triphosphate guanine nucleotide exchange factor, is upregulated in prostate cancer and has been demonstrated to enhance EGF/IGF activation of the AR in the absence of androgen (46).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [46]
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Cook, D. R., Rossman, K. L., & Der, C. J. (2014) · Oncogene · doi:10.1038/onc.2013.362 · Cited by 378 · see citing works
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- Authors
- Lyons, L. S., Rao, S., Balkan, W., Faysal, J., Maiorino, C. A., & Burnstein, K. L.
- Affiliations
- University of Miami (US)
- Department of Molecular and Cellular Pharmacology (L.S.L., S.R., J.F., C.A.M., K.L.B.), Miami, Florida 33136
- Corresponding author
- Burnstein, Kerry L.
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2008-03-01
- Volume
- 22
- Issue
- 3
- Pages
- 597-608
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- PMC
- PMC2262175
- OpenAlex
- W2085254603
- Cited by
- 67
- References
- 58
- Citations by year
- 2025: 6 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 5 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 4 · 2016: 5 · 2015: 4 · 2014: 2 · 2013: 10 · 2012: 6
- FWCI
- 2.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R21DK065281, DK065281)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- androgen receptor, ligand-independent receptor activation, Vav3, Rho GTPases, Rac1, prostate cancer, androgen independence, ERK signaling, growth factor signaling, androgen deprivation therapy, tumor progression
- MeSH terms
- Animals, Humans, Male, Mice, Nude, Neoplasm Transplantation, Neoplasms, Hormone-Dependent, Prostatic Neoplasms, Receptors, Androgen, RNA, Messenger, Transcription, Genetic, Transplantation, Heterologous, Signal Transduction, Up-Regulation, Reverse Transcriptase Polymerase Chain Reaction, Guanine Nucleotide Exchange Factors, rac1 GTP-Binding Protein, Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Cell Line, Tumor, Mice, Proto-Oncogene Proteins c-vav
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