| Prostate cancer is the most common hormone-dependent human malignancies diagnosed in men. Androgen regulates a wide array of genes in prostate growth and development, hence understanding the regulation of these genes may provide clues to prostate carcinogenesis. Using serial analysis of gene expression, we identified the VEGF as an androgen-regulated gene. We showed that human prostate carcinoma LNCaP, PC3 and DU145 cells express VEGF-121 and VEGF-165 and all three VEGF receptors. The levels of VEGF and VEGF-R1 but not VEGF-R2 or VEGF-R3 were up-regulated by DHT (dihydrotestosterone) treatment. This up-regulation required the presence of the androgen receptor (AR). The induction of VEGF-R1 by DHT appeared to be direct since it was not blocked by the treatment of cycloheximide, a protein synthesis inhibitor. The highest induction of VEGF-R1 was seen with 10 nM DHT at 6 hours in LNCaP cells.; Analysis of the human VEGF-R1-Luc promoter construct (−5100 to 1 nucleotide region) showed a moderate but consistent induction by DHT and testosterone in the presence of wild-type AR or T877A mutant AR. No induction was seen, however, in the presence of the L701 H, A748T, H874Y and T877A/L701 H tumor-derived mutant ARs. These mutants did not demonstrate any increase in the VEGF-R1 promoter activity upon further exposure to 17-β-estradiol, progesterone and cortisol, nor a decrease in the activity upon exposure to AR antagonist flutamide and casodex. Our results suggest that the VEGF axis can be up-regulated by androgens and may play a role in the development and progression of prostate cancer. |
