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Androgen-independent growth is induced by neuropeptides in human prostate cancer cell lines
J Jongsma1, M H Oomen, M A Noordzij
1Department of Experimental Urology, Erasmus University, Rotterdam, The Netherlands. jongsma@uro.fgg.eur.nl
Background:
Androgen-independent growth leads to progressive prostate cancer after androgen-ablation therapy. This may be caused by altered specificity of the androgen receptor (AR), by ligand-independent stimulation of the AR, or by paracrine growth modulation by neuropeptides secreted by neuroendocrine (NE) cells.
Methods:
We established and characterized the androgen-independent FGC-DCC from the androgen-dependent LNCaP fast growing colony (FGC) cell line. The androgen-independent DU-145, FGC-DCC, and PC-3, and the androgen-dependent LNCaP and PC-346C cell lines were used to study growth modulation of gastrin-releasing peptide (GRP), calcitonin (CT), serotonin (5-HT), and vasoactive intestinal peptide (VIP) by (3)H-thymidine incorporation. Specificity of the growth-modulating effects was tested with the anti-GRP monoclonal antibody 2A11 and induction of cAMP by neuropeptides.
Results:
Androgen-independent growth stimulation by neuropeptides was shown in DU-145 and PC-346C. 2A11 inhibited GRP-induced (3)H-thymidine incorporation in DU-145 and PC-346C and inhibited proliferation of the FGC-DCC and PC-3 cell lines. With some exceptions, cAMP induction paralleled growth stimulation. Dideoxyadenosine (DDA) inhibited the GRP-induced growth effect in DU-145 and PC-346C, whereas oxadiazoloquinoxaline-1-one (ODQ) had no effect on (3)H-thymidine incorporation. None of the neuropeptides stimulated growth of LNCaP, FGC-DCC, or PC-3.
Conclusions:
GRP-induced growth of DU-145 and PC-346C was specific and cAMP-mediated. Androgen-independent growth of FGC-DCC cells was mainly due to an induction of Bcl-2 expression and possibly through the activation of an autocrine and NE-like pathway, as has been shown also for the PC-3 cell line. Growth induction of non-NE cells by neuropeptides could be a possible role for NE cells in clinical prostate cancer.
Insights
Neuropeptides like gastrin-releasing peptide (GRP) stimulate androgen-independent prostate cancer growth in certain cell lines. Neuroendocrine (NE) cells may play a role in clinical prostate cancer progression.
Area of Science:
- Oncology
- Cell Biology
- Endocrinology
Background:
- Androgen-independent prostate cancer growth is a major challenge after androgen-ablation therapy.
- Potential mechanisms include altered androgen receptor (AR) specificity, ligand-independent AR stimulation, or paracrine growth modulation by neuroendocrine (NE) cells.
- Neuropeptides secreted by NE cells are implicated in prostate cancer progression.
Purpose of the Study:
- To investigate the role of neuropeptides in androgen-independent prostate cancer growth.
- To characterize the growth-modulating effects of specific neuropeptides (gastrin-releasing peptide (GRP), calcitonin (CT), serotonin (5-HT), and vasoactive intestinal peptide (VIP)) on various prostate cancer cell lines.
- To determine the specificity and signaling pathways involved in neuropeptide-mediated growth.
Main Methods:
- Established and characterized the androgen-independent FGC-DCC cell line from the androgen-dependent LNCaP cell line.
- Utilized androgen-independent (DU-145, FGC-DCC, PC-3) and androgen-dependent (LNCaP, PC-346C) prostate cancer cell lines.
- Assessed neuropeptide-induced growth modulation via (3)H-thymidine incorporation, tested specificity using anti-GRP antibody (2A11), and evaluated cAMP induction.
Main Results:
- Neuropeptides stimulated androgen-independent growth in DU-145 and PC-346C cell lines.
- Anti-GRP antibody 2A11 inhibited GRP-induced proliferation in DU-145, PC-346C, FGC-DCC, and PC-3 cells.
- Cyclic adenosine monophosphate (cAMP) induction generally paralleled growth stimulation, with specific inhibitors showing differential effects.
Conclusions:
- Gastrin-releasing peptide (GRP)-induced growth in DU-145 and PC-346C cells is specific and mediated by cAMP.
- Androgen-independent growth of FGC-DCC cells involves Bcl-2 induction and potentially an autocrine, NE-like pathway.
- Neuropeptides may promote the growth of non-NE prostate cancer cells, highlighting a potential role for NE cells in clinical prostate cancer progression.