Androgen-independent growth is induced by neuropeptides in human prostate cancer cell lines

BACKGROUND. Androgen-independent growth leads to progressive prostate cance r after androgen-ablation therapy. This may be caused by altered specificit y of the androgen receptor (AR), by ligand-independent stimulation of the A R, or by paracrine growth modulation by neuropeptides secreted by neuroendo crine (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 gastri n-releasing peptide (GRP), calcitonin (CT), serotonin (5-HT), and vasoactiv e intestinal peptide (VIP) by H-3-thymidine incorporation. Specificity of t he growth-modulating effects was tested with the anti-GRP monoclonal antibo dy 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 H-3-thymidine incorporat ion 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 stimu lation. Dideoxyadenosine (DDA) inhibited the GRP-induced growth effect in D U-145 and PC-346C, whereas oxadiazoloquinoxaline-1-one (ODQ) had no effect on H-3-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 a n induction of Bcl-2 expression and possibly through the activation of an a utocrine 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 rol e for NE cells in clinical prostate cancer. Prostate 42:34-44, 2000. (C) 20 00 Wiley-Liss, Inc.