Aberrant activation of androgen receptor in a new neuropeptide- autocrine model of androgen-insensitive prostate cancer.
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Abstract
Treatment of advanced prostate cancer with androgen deprivation therapy inevitably renders the tumors castration-resistant and incurable. Under these conditions, neuroendocrine differentiation of prostate cancer (CaP) cells is often detected and neuropeptides released by these cells may facilitate the development of androgen independence. Exemplified by gastrin-releasing peptide (GRP), these neuropeptides transmit their signals through G protein-coupled receptors, which are often overexpressed in prostate cancer, and aberrantly activate androgen receptor (AR) in the absence of androgen. We developed an autocrine neuropeptide model by overexpressing GRP in LNCaP cells and the resultant cell line, LNCaP-GRP, exhibited androgen-independent growth with enhanced motility in vitro. When orthotopically implanted in castrated nude mice, LNCaP-GRP produced aggressive tumors, which express GRP, prostate-specific antigen, and nuclear-localized AR. Chromatin immunoprecipitation studies of LNCaP-GRP clones suggest that GRP activates and recruits AR to the cognate promoter in the absence of androgen. A Src family kinase (SFK) inhibitor, AZD0530, inhibits androgen-independent growth and migration of the GRP-expressing cell lines, and blocks the nuclear translocation of AR, indicating the involvement of SFK in the aberrant activation of AR and demonstrating the potential use of SFK inhibitor in the treatment of castration-resistant CaP. In vivo studies have shown that AZD0530 profoundly inhibits tumor metastasis in severe combined immunodeficient mice implanted with GRP-autocrine LNCaP cells. This xenograft model shows autocrine, neuropeptide- and Src kinase-mediated progression of androgen-independent CaP postcastration, and is potentially useful for testing novel therapeutic agents.
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Overexpression of GRP is sufficient to confer LNCaP xenograft tumor growth in castrated mice, in accordance with the observed AR transactivation.
“Overexpression of GRP is also sufficient to confer LNCaP xenograft tumor growth in castrated mice, in accordance with the observed AR transactivation (40).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [40]
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- Authors
- Yang, J. C., Ok, J.-H., Busby, J. E., Borowsky, A. D., Kung, H.-J., & Evans, C. P.
- Affiliations
- 1Urology and Departments of
- University of California, Davis (US)
- 2Biological Chemistry,
- Venue
- Cancer Research
- Published
- 2008-12-31
- Volume
- 69
- Issue
- 1
- Pages
- 151-160
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2626435
- OpenAlex
- W1976784043
- Cited by
- 70
- References
- 51
- Citations by year
- 2026: 1 · 2024: 1 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 1 · 2015: 5 · 2014: 7 · 2013: 12 · 2012: 6
- FWCI
- 8.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Defense
- Tulane University
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK52659, K08DK060748, K08 DK60748-01, R01DK052659)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- androgen receptor, castration-resistant prostate cancer, gastrin-releasing peptide, neuropeptides, autocrine signaling, neuroendocrine differentiation, Src family kinases, AZD0530, androgen-independent growth, metastasis, LNCaP cells, G protein-coupled receptors
- MeSH terms
- Animals, Cell Movement, Enzyme Activation, Genetic Vectors, Humans, Male, Mice, Nude, Neoplasms, Hormone-Dependent, Prostatic Neoplasms, Protein-Tyrosine Kinases, Quinazolines, Receptors, Androgen, Transfection, Mice, SCID, src-Family Kinases, Gastrin-Releasing Peptide, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Growth Processes, Mice, Focal Adhesion Kinase 1, Benzodioxoles, Androgen Receptor Antagonists
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