Androgen-independent growth is induced by neuropeptides in human prostate cancer cell lines.
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.
Jongsma
J
J
Department of Experimental Urology, Erasmus University, Rotterdam, The Netherlands. jongsma@uro.fgg.eur.nl
Oomen
M H
MH
Noordzij
M A
MA
Romijn
J C
JC
van Der Kwast
T H
TH
Schröder
F H
FH
van Steenbrugge
G J
GJ
D000728:Androgens / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D000242:Cyclic AMP / Q000502:physiology; D016048:Dideoxyadenosine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019886:Gastrin-Releasing Peptide / Q000494:pharmacology; D006801:Humans; D008297:Male; D009479:Neuropeptides / Q000502:physiology*; D010069:Oxadiazoles / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000728:Androgens; D004791:Enzyme Inhibitors; D009479:Neuropeptides; D010069:Oxadiazoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011810:Quinoxalines; D016048:Dideoxyadenosine; D019886:Gastrin-Releasing Peptide; D000242:Cyclic AMP; D013936:Thymidine