Aberrant Activation of Androgen Receptor in a New Neuropeptide-Autocrine Model of Androgen-Insensitive Prostate Cancer
| Autor: | Alexander D. Borowsky, J. Erik Busby, Christopher P. Evans, Joon Ha Ok, Hsing Jien Kung, Joy C. Yang |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Cancer Research medicine.medical_specialty Neoplasms Hormone-Dependent medicine.drug_class Genetic Vectors Mice Nude Cell Growth Processes Mice SCID Biology Transfection urologic and male genital diseases Neuroendocrine differentiation Article Androgen deprivation therapy Mice Prostate cancer Cell Movement Cell Line Tumor Gastrin-releasing peptide Internal medicine LNCaP Androgen Receptor Antagonists medicine Animals Humans Benzodioxoles Prostatic Neoplasms Protein-Tyrosine Kinases Androgen medicine.disease Xenograft Model Antitumor Assays Enzyme Activation Androgen receptor src-Family Kinases Endocrinology Gastrin-Releasing Peptide Oncology Receptors Androgen Focal Adhesion Kinase 1 Quinazolines Cancer research hormones hormone substitutes and hormone antagonists |
| Zdroj: | Cancer Research. 69:151-160 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-08-0442 |
| Popis: | 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. [Cancer Res 2009;69(1):151–60] |
| Databáze: | OpenAIRE |
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