EXPRESSION OF DIFFERENT 17-BETA-HYDROXYSTEROID DEHYDROGENASE TYPES AND THEIR ACTIVITIES IN HUMAN PROSTATE-CANCER CELLS

The 17 beta-hydroxysteroid dehydrogenase (17 beta HSD) enzyme system g overns important redox reactions at the C17 position of steroid hormon es. Different 17 beta HSD types (no. 1-4) have been identified to date in peripheral human tissues, such as placenta, testis, and breast. Ho wever, there is little information on their expression and activity in either normal or malignant prostate. In the present work, we have Ins pected pathways of 17 beta-oxidation of either androgen or estrogen in human prostate cancer cells (LNCaP, DU145, and PC3) in relation to th e expression of messenger RNAs (mRNAs) for 17 beta HSD types 1-4. Thes e cell systems feature distinct steroid receptor status and response t o hormones. We report here that high expression levels of 17 beta HSD4 were consistently observed in all three cell lines, whereas even grea ter amounts of 17 beta HSD2 mRNA were detected solely in PC3 cells. Ne ither 17 beta HSD1 nor 17 beta HSD3 mRNAs could be detected in any cel l line. From a metabolic standpoint, intact cell analysis showed a muc h lower extent of 17 beta-oxidation of both androgen [testosterone (T) ] and estrogen [estradiol(E-2)] in LNCaP and DU145 cells compared to P C3 cells, where a greater precursor degradation and higher formation r ates of oxidized derivatives (respectively, androstenedione and estron e) were observed. Using subcellular fractionation, we have been able t o differentiate among 17 beta HSD types 1-4 on the basis of their dist inct substrate specificities and subcellular localization. This latter approach gave rise to equivalent results. PC3 cells, in fact, display ed a high level of microsomal activity with a low E-2/T activity ratio and approximately equal apparent K-m values for E-2 and T, suggesting the presence of 17 beta HSD2. Dehydrogenase specific activity with bo th E-2 and T was also detected, although at lower levels, in LNCaP and DU145 cells. No evidence for reductase activity could be obtained in either the soluble or microsomal fraction of any cell line, As compara ble expression levels of 17 beta HSD4 were seen in the three cell line s, 17 beta HSD2 is a likely candidate to account for the predominant o xidative activity in PC3 cells, whereas 17 beta HSD4 may account for t he lower extent of E-2 oxidation seen in both LNCaP and DU145 cells. T his is the first report on the expression of four different 17 beta HS D types in human prostate cancer cells. It ought to be emphasized that for the first time, analysis of different 17 beta HSD activities in e ither intact or fractionated cells harmonizes with the expression of r elevant mRNAs species.