Synergistic activation of the androgen receptor by bombesin and low-dose androgen

Jie Dai, Ruoqian Shen, Makoto Sumitomo, Rosalyn Stahl, Daniel Navarro, Marvin C. Gershengorn, David M. Nanus

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36 Citations (Scopus)

Abstract

Purpose: Neuropeptide growth factors such as bombesin are 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.

Original languageEnglish
Pages (from-to)2399-2405
Number of pages7
JournalClinical Cancer Research
Volume8
Issue number7
Publication statusPublished - 01-01-2002
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Dai, J., Shen, R., Sumitomo, M., Stahl, R., Navarro, D., Gershengorn, M. C., & Nanus, D. M. (2002). Synergistic activation of the androgen receptor by bombesin and low-dose androgen. Clinical Cancer Research, 8(7), 2399-2405.