Selective reduction of AKR1C2 in prostate cancer and its role in DHT metabolism

BACKGROUND. As androgens play an essential role in prostate cancer, we sought to develop a real-time PCR to characterize mRNA expression profiles of human members of the Aldo-Keto Reductase (AKR) 1C gene family, as well as of 5alpha-steroid reductase Type II (SRD5A2) in prostate cancer samples. Functional activity and regulation of AKR1C2, a 3(X-hydroxysteroid dehydrogenase (HSD) type III, was also assessed in prostate cancer cell lines. METHODS. Gene specific PCR primers were established and relative gene expression of human AKR1C family members was determined in paired samples of cancerous and surrounding unaffected prostate tissue. RESULTS. AKR1C2 preferentially reduces DHT to the weak metabolite 5alpha-androstane-3alpha,17beta-diol 3alpha-diol) without conversion of 3alpha-diol to DHT in the PC-3 cell line, and its expression was increased by DHT treatment in LNCaP cells. Selectively reduced expression of AKR1C2 mRNA, but not AKR1C1 (97% sequence identity), was found in approximately half of the pairs whereas AKR1C3 relative expression was not significantly altered. No aberrant expression of AKR1C4 expression or significant differences in SRD5A2 gene expression were found. CONCLUSIONS. AKR1C2 functions as a DHT reductase in prostate-derived cells lines and is regulated by DHT. Additional studies are needed to further define the significance of reduced AKR1C2 expression in prostate cancer and its potential role in modulating local availability of DHT. Prostate 54: 275-289,2003. (C) 2003 Wiley-Liss, Inc.