Synergistic Activation of the Androgen Receptor by Bombesin and Low-Dose Androgen

Purpose: Neuropeptide growth factors such as bombesinare implicated in progression to androgen-independent prostate cancer (PC). We examined the impact of bombesin on androgen receptor (AR)-mediated gene expression. Experimental Design: The AR together with the AR-responsive probasin ARR 3 tk-luc or PSA-pPUE-ELB-luc promoter was cotransfected into Swiss 3T3 and PC-3 cells, both of which express high-affinity bombesin receptors; the cells were incubated with bombesin (0–50 nm) and dihydrotestosterone (DHT; 0–10 nm), and luciferase activities were measured. DHT increased transcription ∼40-fold at doses of 1 and 10 nm but had no effect at 10 pm. Bombesin alone, or with 1 or 10 nm DHT, did not further increase transcription. However, 5 nm bombesin and 10 pm DHT, doses that by themselves had no effect, resulted in a ∼20 fold increase in transcription ( P 32 P-labeled LNCaP cells revealed that 5 nm bombesin + 10 pm DHT induced AR phosphorylation comparable with 1 nm DHT, whereas bombesin or 10 pm DHT alone did not. Conclusions: These data indicate that bombesin can synergize with low (castrate) levels of DHT to induce AR-mediated transcription and suggest that neuropeptides promote AR-mediated signaling in androgen-independent prostate cancer.