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Updated: Aug 13, 2026
An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 18, 2013
GnRH agonists and antagonists decrease the metastatic progression of human prostate cancer cell lines by inhibiting
D Dondi1, C Festuccia, M Piccolella
1Department of Endocrinology, Center of Endocrinological Oncology, University of Milano, Via Balzaretti 9, 20133 Milano, Italy. donatella.dondi@unimi.it
Abstract:
Prostate cancer (PCa) growth initially depends on circulating androgens. Gonadotropin-releasing hormone (GnRH) agonists are currently used for the treatment of PCa. However, after an initial responsiveness to hormonal deprivation, PCa progresses and metastasizes. Recently, also GnRH antagonists have been used for clinical trials in patients with PCa and the results seem promising. The components of the plasminogen activator (PA) system (urokinase-type PA, uPA; PA inhibitors, PAI-1/2; uPA receptor, uPAR) have been implicated in the local degradation of the extracellular matrix (ECM) and PCa progression. The aim of this study was to test the possible effects of the treatment with an agonist (Leuprolide, GnRH-A) and an antagonist (Cetrorelix, GnRH-ANT) of GnRH on the expression and activity of uPA and PAI-1 in the conditioned media of DU145 and PC3, two PCa androgen-independent cell lines. The involvement of the PA system in the control of cellular migration was also investigated. The results obtained in DU145 and PC3 cells show that both GnRH-A and GnRH-ANT: i) inhibit cell proliferation; ii) significantly decrease the enzymatic activity and the secretion of uPA; iii) significantly increase the protein levels of PAI-1; iv) induce a significant decrease of the migratory and invasion PCa capabilities. This study suggests that GnRH analogues exhibit not only an antiproliferative effect, but also an anti-metastatic action exerted through the inhibition of the activity of PA system and might provide a rational basis for the development of clinical strategies for those tumours that progress towards an androgen-independent condition characterized by a higher metastatic potential.
Insights
Gonadotropin-releasing hormone (GnRH) agonists and antagonists reduce prostate cancer cell proliferation and metastasis by inhibiting urokinase-type plasminogen activator (uPA) activity and increasing its inhibitor (PAI-1). These findings support GnRH analogues as treatments for advanced prostate cancer.
Area of Science:
- Oncology
- Endocrinology
- Biochemistry
Background:
- Prostate cancer (PCa) growth is initially androgen-dependent, but it progresses to an androgen-independent, metastatic state.
- Gonadotropin-releasing hormone (GnRH) analogues are used to treat PCa, but resistance develops.
- The plasminogen activator (PA) system, including urokinase-type PA (uPA) and its inhibitor PAI-1, is involved in extracellular matrix degradation and cancer progression.
Purpose of the Study:
- To investigate the effects of GnRH agonist (Leuprolide) and antagonist (Cetrorelix) on uPA and PAI-1 in androgen-independent PCa cell lines (DU145, PC3).
- To assess the impact of GnRH analogues on the migratory and invasive potential of PCa cells, mediated by the PA system.
Main Methods:
- Treatment of DU145 and PC3 prostate cancer cell lines with GnRH agonist (GnRH-A) and GnRH antagonist (GnRH-ANT).
- Measurement of cell proliferation, uPA enzymatic activity, uPA secretion, and PAI-1 protein levels in conditioned media.
- Evaluation of cellular migration and invasion capabilities.
Main Results:
- Both GnRH-A and GnRH-ANT significantly inhibited cell proliferation in DU145 and PC3 cells.
- GnRH analogues markedly decreased uPA enzymatic activity and secretion.
- Treatment with GnRH analogues led to a significant increase in PAI-1 protein levels.
- GnRH analogues significantly reduced the migratory and invasive potential of PCa cells.
Conclusions:
- GnRH analogues demonstrate antiproliferative effects on androgen-independent prostate cancer cells.
- GnRH analogues possess anti-metastatic properties by inhibiting the PA system's activity.
- These findings suggest GnRH analogues could be a therapeutic strategy for advanced, metastatic prostate cancer with potential clinical applications.
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