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Synergistic Activation of the Androgen Receptor by Bombesin and Low-Dose Androgen¹

Urologic Oncology Research Laboratory, Department of Urology [J. D., R. S., M. S., R. S., D. N., D. M. N.], Division of Hematology and Medical Oncology [D. M. N.], Joan and Stanford I. Weill Medical College, Cornell University, New York, New York 10021, and National Institutes of Health, Bethesda, Maryland 20892 [M. C. G.]

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 ARR₃tk-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 < 0.005). This synergistic effect was blocked by bombesin receptor antagonists and recombinant neutral endopeptidase, which hydrolyzes bombesin. Bombesin and DHT together also increased binding of nuclear extracts from PC-3 cells transfected with AR to a consensus androgen response element in mobility shift assays and increased the level of secreted prostate-specific antigen in LNCaP cell supernatant compared with DHT or bombesin alone. Immunoprecipitation of AR from ³²P-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.

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