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Expression of Different 17ß-Hydroxysteroid Dehydrogenase Types and Their Activities in Human Prostate Cancer Cells¹

Institute of Oncology (L.A.M.C., G.C.) and Institute of Urology (M.P.-M.), Policlinico, University Medical School; and Experimental Oncology and Molecular Endocrinology Units, Palermo Branch of the National Cancer Institute of Genoa (L.A.M.C., A.T., O.M.G.), Cancer Hospital Center, Palermo, Italy; Max Planck Institute for Experimental Endocrinology (M.M.), Hannover, Germany; and GSF- National Research Center, Institute of Mammalian Genetics (J.A.), Neuherberg, Germany; and the Department of Obstetrics and Gynecology, Healthpartners for Environment and Health, St. Paul-Ramsey Medical Center (C.H.B.), St. Paul, Minnesota 55101-2595

Address all correspondence and requests for reprints to: Dr. Luigi A. M. Castagnetta, Istituto di Oncologia, Università di Palermo, Via Marchese Ugo 56, 90141 Palermo, Italy.

The 17ß-hydroxysteroid dehydrogenase (17ßHSD) enzyme system governs important redox reactions at the C17 position of steroid hormones. Different 17ßHSD types (no. 1–4) have been identified to date in peripheral human tissues, such as placenta, testis, and breast. However, there is little information on their expression and activity in either normal or malignant prostate. In the present work, we have inspected pathways of 17ß-oxidation of either androgen or estrogen in human prostate cancer cells (LNCaP, DU145, and PC3) in relation to the expression of messenger RNAs (mRNAs) for 17ßHSD types 1–4. These cell systems feature distinct steroid receptor status and response to hormones. We report here that high expression levels of 17ßHSD4 were consistently observed in all three cell lines, whereas even greater amounts of 17ßHSD2 mRNA were detected solely in PC3 cells. Neither 17ßHSD1 nor 17ßHSD3 mRNAs could be detected in any cell line. From a metabolic standpoint, intact cell analysis showed a much lower extent of 17ß-oxidation of both androgen [testosterone (T)] and estrogen [estradiol (E₂)] in LNCaP and DU145 cells compared to PC3 cells, where a greater precursor degradation and higher formation rates of oxidized derivatives (respectively, androstenedione and estrone) were observed. Using subcellular fractionation, we have been able to differentiate among 17ßHSD types 1–4 on the basis of their distinct substrate specificities and subcellular localization. This latter approach gave rise to equivalent results. PC3 cells, in fact, displayed a high level of microsomal activity with a low E₂/T activity ratio and approximately equal apparent K_m values for E₂ and T, suggesting the presence of 17ßHSD2. Dehydrogenase specific activity with both E₂ 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 comparable expression levels of 17ßHSD4 were seen in the three cell lines, 17ßHSD2 is a likely candidate to account for the predominant oxidative activity in PC3 cells, whereas 17ßHSD4 may account for the lower extent of E₂ oxidation seen in both LNCaP and DU145 cells. This is the first report on the expression of four different 17ßHSD types in human prostate cancer cells. It ought to be emphasized that for the first time, analysis of different 17ßHSD activities in either intact or fractionated cells harmonizes with the expression of relevant mRNAs species.

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