Hypoxia and the androgen receptor (AR) play important roles in the development and progression of prostate cancer. In this study, the combined effects of dihydrotestosterone (DHT) and hypoxia on AR-mediated transactivation were investigated. Hypoxia alone did not induce a detectable ARE-mediaced response in the absence of DHT. DHT-induced AR transcriptional activity was dramatically increased by hypoxia or ectopic expression of HIF-1 alpha, as determined by introducing ARE-responsive reporter plasmids into LNCaP prostate cancer cells. The secretion of VEGF was enhanced by the combination of hypoxia and DHT as compared to each treatment alone. These effects were not due to increased expression of the AR or HIF-1 alpha as a result of hypoxia and DHT treatment. These results provide evidence that hypoxia may stimulate as yet unknown factors, which further stimulate AR signal transduction pathways. (C) 2012 Elsevier Inc. All rights reserved.