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Messenger Ribonucleic Acid Levels of Steroid 5-Reductase 2 in Human Prostate Predict the Enzyme Activity¹

Departments of Medical Laboratory Sciences and Technology (T.G.S., C.B., B.A., A.R.), Karolinska Institutet, Division of Clinical Pharmacology, Huddinge University Hospital, SE-14186, Huddinge; Stockholm Pathology and Cytology (L.E.), Karolinska Hospital, SE-171 76, Stockholm; and Urology (E.B., B.J.N.), Uppsala University Hospital, SE-751 85, Uppsala, Sweden

Address all correspondence and requests for reprints to: Torbjörn Söderström, Department of Clinical Pharmacology, Huddinge University Hospital C168, S-141 86 Huddinge, Sweden. E-mail: torbjorn.soderstrom{at}medsci.uu.se

	Abstract

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Testosterone is converted to dihydrotestosterone by 5-reductase2 in the prostate. Dihydrotestosterone controls cell division, and interindividual differences in prostatic 5-reductase 2 expression and activity may be a determinant of the risk of developing prostate cancer. However, little is known about interindividual differences in intraprostatic hormonal activity in vivo. To determine whether 5-reductase-specific messenger RNA (mRNA) is predictive of 5-reductase activity in prostatic tissue, we analyzed 30 prostatic tissue specimens from 15 Caucasian patients, 47–82 yr old. The mRNA was measured by RT-PCR. Five specimens consisted of cancer, whereas the remaining 25 were derived from benign prostate hyperplasia (BPH).

We found a strong association between enzyme activity at pH 5.5 and the 5-reductase 2-specific mRNA expression when expressed on the basis of ß-actin [Spearman’s rank-correlation coefficient (r_s) = 0.81; 95% confidence interval, 0.64–0.91; P < 0.0001]. The expression of 5-reductase 2-specific mRNA in the cancer specimens was significantly lower than in the BPH tissue (P = 0.03). There was no difference in the expression of 5-reductase 1-specific mRNA in the cancer specimens, compared with BPH (P = 0.56). The strong association between 5-reductase activity at pH 5.5 and the 5-reductase 2-specific mRNA expression makes it possible to predict prostatic 5-reductase activity using core needle biopsies.

	Introduction

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PROSTATE CANCER IS a significant public health problem in the western world. In Sweden, prostate cancer is the most frequent cancer and the primary cause of cancer deaths among men (1). Androgens play a pivotal role in prostate carcinogenesis. Cell division in the prostate is controlled by dihydrotestosterone (DHT) (2), which has a greater affinity for the androgen receptor than testosterone (3). Testosterone is converted to DHT by the enzyme 5-reductase. Two distinct isoforms, types 1 and 2, encoded by different genes, have been cloned (4, 5). They differ with respect to pH optima in vitro and have differential sensitivity to inhibitors such as finasteride (6). The endogenous elimination rate of the isozymes corresponds to half-lives of 45 and 80 h for types 1 and 2, respectively (7). The two isozymes show tissue-specific expression with type 1, expressed predominantly in sebaceous glands, in nongenital skin, and in the liver (8). Type 2 is expressed in the prostate, epididymis, seminal vesicle, genital skin, and liver (6). The support for the conclusion that 5-reductase 2 is the major isozyme in the prostate comes from genetic (5, 9, 10), pharmacological (11, 12, 13), biochemical (14, 15), and immunohistochemical studies (14, 15). In contrast, the activity of 5-reductase 1 is undetectable in the prostate (8), although low levels of type 1 messenger RNA (mRNA) have been detected (4, 16). Immunohistochemical mapping has demonstrated that the 5-reductase 1 is localized in the basal portion of basal and epithelial cells (8).

It is hypothesized that DHT acts in a paracrine manner, based on the findings that 5-reductase type 2 is localized perinuclearly within stromal and basal epithelial cells rather than in the androgen-dependent luminal epithelial cells (17).

Interindividual differences in prostatic 5-reductase 2 expression and activity may be a determinant of the risk of developing clinical prostate cancer and eventually dying from it. Data on serum levels of DHT metabolites support the hypothesis that variation in the 5-reductase activity may explain part of the population differences in prostate cancer incidence (18). However, little is known about interindividual differences in intraprostatic hormonal activity in vivo. A substantial problem for prospective studies has been the need for surgical biopsies of appropriate size for metabolic assays.

Our primary goal was to determine whether 5-reductase 2-specific mRNA expression, as assessed by RT-PCR, predicts 5-reductase activity in prostatic tissue. Our results support such a predictive value of the enzyme-specific mRNA level in the prostate and also demonstrate a considerable variation in expression of the 5-reductase 2 gene in prostatic tissue between (untreated) subjects.

	Subjects and Materials

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Patients

Thirty prostatic tissue specimens were obtained, at surgery, from 15 Caucasian patients (age, 47–82 yr; median, 66). Five patients were enucleated because of benign prostate hyperplasia (BPH), and 10 underwent total prostatectomy because of bladder or prostate cancer. The tissue specimens were immediately frozen on dry ice and stored at -70 C until RNA extraction. A pathologist (L. Egevad) reviewed frozen sections from the specimens. Five specimens from different patients consisted of cancer (Gleason grade 6–7; median, 6), whereas the remaining 25 were derived from BPH. Four lymph node biopsies from 3 patients with prostate cancer were obtained. These nodes did not contain any cancer metastases.

Chemicals and reagents

[¹⁴C]-testosterone (SA, 56 Ci/mmol) was purchased from Amersham Pharmacia Biotech (Little Chalfont, Buckinghamshire, UK) and [¹⁴C]-DHT (56.6 Ci/mmol) from NEN Life Science Products (Boston, MA). All other chemicals were from Sigma (St. Louis, MO), except dithiothreitol (DTT), which was purchased from Roche Molecular Biochemicals GmbH (Mannheim, Germany). Taq DNA polymerase was purchased from Appligene (Illkirch, France). All other enzymes used were from Promega Corp. (Madison, WI).

Tissue preparation

Tissues were pulverized in liquid nitrogen using mortar and pestle. Half of the material was used for mRNA preparation, and the other half was homogenized according to Ellsworth and Harris (19) for metabolic assays. Protein concentration was measured according to Lowry et al. (20).

5-Reductase assay in vitro

The assays are modified variants of a method published by Ellsworth and Harris (19). The 5-reductase 2 activity, at pH 5.5, was assayed in a mixture containing 33 mmol/L succinate, 44 mmol/L imidazol, 33 mmol/L diethylamine, 40 mmol/L potassium phosphate (pH 5.5), 0.2 nmol/L ¹⁴C-testosterone, 1 mmol/L DTT, and 500 µmol/L NADPH in a final vol of 100 µL. The reaction was started by addition of the enzyme preparation at a final protein concentration of 0.5 mg/mL and then incubated at 37 C for 10 min.

The 5-reductase 1 activity, at pH 7.0, was analyzed as described above, except for the use of 40 mmol/L potassium phosphate (pH 7.0), 1 nmol/L ¹⁴C-testosterone, and an incubation time of 5 min. The reactions were stopped by extraction with 300 µL of a mixture of cyclohexane: ethyl acetate (70/30, vol/vol) containing 12 µg each of DHT and testosterone. Testosterone was separated from DHT using thin layer chromatography (21). The formation of DHT was analyzed using a Phosphor Imager (Molecular Dynamics, Inc., Little Chalfont, Buckinghamshire, UK). The assay was validated in terms of linearity with protein concentration, incubation time, and substrate concentration.

Total RNA (totRNA) purification

totRNA was extracted from frozen pulverized prostatic tissue (see above) using a guanidium thiocyanate-phenol-chloroform extraction method (22).

RT-PCR

The following primers, obtained from DNA Technology (Aarhus, Denmark), were used: 5-reductase 2 forward: 5'-ATT GCG CCA GCT CAG GAA G-3', 5-reductase 2 reverse: 5'-TGG AAT AAG GGC TTT CCG AGAT-3', 5-reductase 1 forward: 5'-GCG AGG AGG AAA GCC TAT GC-3', 5-reductase 1 reverse: 5'-CAG GGC ATA GCC ACA CCA CT-3', ß-actin forward: 5'-GTA CCC TGG CAT TGC CGA C-3', and ß-actin reverse: 5'-TAA CGC AAC TAA GTC ATA GTCC-3'.

The primer pairs were chosen in different exons to detect DNA contamination. After isolation of RNA, mRNA was reverse transcribed using the first-strand complementary DNA synthesis kit (Pharmacia Biotech, Uppsala, Sweden), following the manufacturer’s instructions. Forty picomoles of specific reverse primer and 1 mg totRNA were used in each reaction. The PCR reactions were performed in a Thermocycler PTC-200 (SDS, Falkenburg, Sweden) as follows: 95 C for 4 min followed by 35 cycles at 95 C for 30 sec; 55 C for 1 min and 72 C for 1 min; and finally, a 5-min extension step after the final cycle. The PCR reaction mixture contained 40 pmol of specific primers, 13.5 mmol/L Tris (pH 8.3), 20 mmol/L KCl, 4.5 mmol/L DTT, 2.7 mmol/L MgCl₂, 0.02 mg/mL BSA, and 0.6 mmol/L each of deoxy-ATP, deoxycytidine triphosphate, deoxyguanosine 5'-triphosphate, deoxythymidine triphosphate, and 2.5 u Taq DNA polymerase. Samples were analyzed for both 5a-reductase and ß-actin in simultaneous parallel PCR reactions. Control samples containing water instead of totRNA were included in each run. The linearity of the PCR amplifications was determined by varying the number of cycles and the amount of complementary DNA in the reaction. The PCR products were analyzed on a 2% agarose gel and visualized by ethidium bromide. The different primer pairs that were used yielded a 258-bp fragment corresponding to 5-reductase 2, a 316-bp fragment corresponding to 5-reductase 1, and a 240-bp fragment corresponding to ß-actin. The gels were photographed with a computerized Gel Doc 1000 video gel documentation system (Bio-Rad Laboratories, Inc.). The intensity of the bands was measured with Molecular Analyst software, version 1.5 (Bio-Rad Laboratories, Inc., Hercules, CA). The semiquantitative determination of the 5-reductase 1 and 2 mRNA levels was made on the basis of the corresponding ß-actin mRNA level and is presented as the ratio between the intensity values of the respective bands.

Evaluation of data

The statistical evaluation was made using StatView for Windows software, version 4.57 (Abacus Concepts Inc., North Carolina). The Mann-Whitney test was used for comparisons between groups. Spearman’s rank-correlation coefficient was used in the evaluation of association.

	Results

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5-Reduction activity was assayed in duplicate in 30 prostate specimens from 15 different patients at pH 5.5 and 7.0. The specimen activity values represent means from duplicate samples. The SDs of the difference between duplicates were 4.2 (DHT, pmol/mg·min) at pH 5.5 and 4.8 at pH 7.0, respectively. There was a strong correlation between the enzyme activity at pH 5.5, compared with pH 7.0 [Spearman’s rank-correlation coefficient (r_s) = 0.79, P < 0.001], indicating that the activity at the latter pH was probably attributable to the 5-reductase 2 enzyme. Four lymph node biopsies from 3 patients with prostate cancer were also investigated, but no 5-reductase activity was detectable in these specimens, which contained benign tissue only.

5-Reductase 2-specific mRNA was consistently present in 29 of the 30 investigated samples. Shown in Fig. 1 are RT-PCR products of prostatic 5-reductase 2-specific and ß-actin-specific mRNA in 14 of the specimens. The ratios between 5-reductase 2 and ß-actin mRNA concentrations varied between 0 (undetectable) and 1.31, with a median of 0.42. The four lymph node specimens did not contain any measurable amounts of enzyme mRNA, but there was a consistent expression of the ß-actin gene. There was a strong association between enzyme activity at pH 5.5 and the 5-reductase 2-specific mRNA expression (Fig. 2), as expressed on the basis of ß-actin (r_s = 0.81; 95% confidence interval, 0.64–0.91; P < 0.0001). The expression of 5-reductase 2-specific mRNA in the cancer specimens was significantly lower than in the BPH tissue (P = 0.03) (Fig. 3). The enzyme activity in the cancer specimens was also significantly lower than in the BPH specimens, when compared at pH 5.5 (P = 0.04), which is the optimum pH for 5-reductase 2 activity in vitro (Fig. 3, Table 1). When assessed separately, the 25 BPH specimens still showed a strong association between enzyme activity at pH 5.5 and the 5-reductase 2-specific mRNA expression (r_s = 0.84, P < 0.0001).

View larger version (79K): [in this window] [in a new window]   Figure 1. 5-reductase 2 and ß-actin-specific mRNA in 14 different prostate specimens from 10 patients [lanes 1 (left)-14] and 4 lymph node specimens from 3 patients (lanes 15–18). The mRNAs were assessed by RT-PCR, and the PCR products were separated in a 2% agarose gel. Upper row, Variable expression of 5-reductase 2; lower row, less variable expression of ß-actin. No expression of 5-reductase 2 mRNA was observed in lymph nodes.

View larger version (17K): [in this window] [in a new window]   Figure 2. Scatter plot, showing the strong association between enzyme activity at pH 5.5 and the 5-reductase 2-specific mRNA expression, as expressed on the basis of ß-actin (n = 30; rs = 0.81; 95% confidence interval, 0.64–0.91; P < 0.0001).

View larger version (17K): [in this window] [in a new window]   Figure 3. Box plots, showing 5-reduction activity with testosterone as substrate at pH 5.5, corresponding to 5-reductase 2 activity (lower panel) and 5-reductase 2/ß-actin mRNA ratios (upper panel) measured in prostate cancer tissue (n = 5) and tissue with BPH (n = 25). The enzyme activity and the 5-reductase 2/ß-actin mRNA ratios were significantly lower in the cancer specimens, compared with BPH (P = 0.04 and 0.03, respectively).

View this table: [in this window] [in a new window]   Table 1. The median and range of 5-reductase activity at acidic and neutral pH in BPH and cancer tissue, expressed as picomoles of dihydrotestosterone formed per milligram of protein per minute

	Discussion

Top Abstract Introduction Subjects and Materials Results Discussion References

 
Our data indicate that 5-reductase 2 enzyme activity is regulated at a transcriptional level in the prostate. The relative concentration of 5-reductase 2-specific mRNA, on the basis of ß-actin, predicts the 5-reductase activity in the prostate. This mRNA-enzyme activity correlation has only briefly been discussed earlier (14) but not characterized. In concordance with earlier results reported by us (23) and others (24), we found the expression of 5-reductase 2-specific mRNA to be lower in cancer tissue, compared with BPH.

We did not see any correlation between activity and mRNA of the 5-reductase 1 enzyme within the prostate. The significance of the presence of 5-reductase 1 mRNA in the prostate is not yet established. The lack of correlation to expression of 5-reductase 2 indicates that these genes are differently regulated in the prostate. Interestingly, we found no evidence of differential expression of the 5-reductase 1 gene between malignant and benign tissue. Further studies are needed to confirm that 5-reductase 1 is of minor relevance in prostate cancer tissue.

Our assessment of mRNA expression of the enzymes was based on the ß-actin mRNA. We found an almost invariable expression of ß-actin in all samples. This demonstrates the good quality of the isolated mRNA, as well as the stability of ß-actin gene expression. All samples were usable for our purposes.

Our data show that it is possible to make a gross estimation of the intraprostatic 5-reductase 2 activity by measuring the mRNA expression. The prostate is not a histologically homogeneous organ but is partitioned into three different zones (25). The peripheral zone is considered to be the site of origin of cancers, whereas the transitional zone is the primary site of hyperplastic growth in BPH. However, the mRNA expression of 5-reductase types 2 and 1 does not seem to vary between the zones, as recently reported (24).

The 5-reductase 2 is preferentially expressed in the stroma of the prostate. We measured the specific mRNA expression in totRNA extracted from a preparation containing all cell types. Therefore, the variation between the samples could theoretically be attributable to the relative contribution of epithelium and stroma, rather than differential expression. Nevertheless, the 5-reductase 2-specific mRNA reflects the tissue capacity to metabolize testosterone into DHT.

Several mutations in the coding region of the 5-reductase 2 gene have been identified (6, 26), many of them leading to 5-reductase deficiency syndrome. At least two of them, V89L and A49T, seem to modulate the 5-reductase activity in vivo only moderately (26). A recent report suggests an association of the A49T missense substitution in the 5-reductase 2 gene with risk of prostate cancer in African-American and Hispanic men (27). The A49T mutation altered the in vitro V_max for testosterone from 1.9 to 9.9 (nmol min^-1 mg^-1) and the Km from 0.9 to 2.7 (µmol/L) (27). This mutation may thus contribute to the interindividual differences in 5-reductase 2 activity. It also shows a possible source of interference with the relationship between specific mRNA expression and enzyme activity. However, the proportion of prostate cancer cases with advanced disease carrying the A49T mutation was reported to be only 10–13%, giving no explanation for the etiology for the vast majority of patients (27). The reported changes in enzyme activity for the mutations V89L and A49T are small, in comparison with the differences in enzyme activity, depending on differential mRNA expression patterns. The degree of expression of 5-reductase 2 and the factors regulating it might therefore be of great interest in further exploration of the etiology of prostate cancer.

Assessment of 5-reductase 2 mRNA expression in core needle biopsies of the prostate (23) may prove useful for evaluation of the impact on prostate 5-reductase 2 expression of different endocrine intervention therapies, as well as other therapies used for treatment of prostate cancer. The possibility of using 5-reductase 2 mRNA expression as a prognostic marker in prostate cancer also needs further evaluation.

	Acknowledgments

 
We thank Ms. Christina Färenmark for technical assistance and Prof. Christer Busch (Department of Pathology, University Hospital, Tromsö, Norway) for valuable discussions.

	Footnotes

 
¹ Supported by the Swedish Cancer Society, Lions Cancer Foundation, the Selander Foundation, the Emil and Ragna Börjesson Memorial Fund, and The Björn Lindström memorial fund.

Received May 5, 2000.

Revised October 4, 2000.

Accepted October 17, 2000.

	References

Top Abstract Introduction Subjects and Materials Results Discussion References

 

1. Statistical Central Bureau, Sweden. 1995 Causes of death 1993. Stockholm.
2. Hashiba T, Noguchi S, Tsuchiya F, et al. 2000 Serum free coculture of stromal and epithelial cells from benign prostatic hyperplasia with keratinocyte growth factor. Urol Int. 64:209–212.
3. Wilbert DM, Griffin JE, Wilson JD. 1983 Characterization of the cytosol androgen receptor of the human prostate. J Clin Endocrinol Metab. 56:113–120.[Abstract]
4. Andersson S, Russell DW. 1990 Structural and biochemical properties of cloned and expressed human and rat steroid 5 -reductases. Proc Natl Acad Sci USA. 87:3640–3644.[Abstract/Free Full Text]
5. Andersson S, Berman DM, Jenkins EP, Russell DW. 1991 Deletion of steroid 5-reductase 2 gene in male pseudohermaphroditism. Nature. 354:159–161.[CrossRef][Medline]
6. Russel DW, Wilson JD. 1994 Steroid 5 -reductase: two genes/two enzymes. Annu Rev Biochem. 63:25–61.[Medline]
7. Gisleskog PO, Hermann D, Hammarlund-Udenaes M, Karlsson MO. 1998 A model for the turnover of dihydrotestosterone in the presence of the irreversible 5 -reductase inhibitors GI198745 and finasteride. Clin Pharmacol Ther. 64:636–647.[CrossRef][Medline]
8. Patel S, Einstein M, Geissler W, Wu L, Andersson S. 1996 Immunohistochemical analysis of steroid 5 -reductase type 1 in human scalp and prostate. Ann NY Acad Sci. 784:27–39.[Medline]
9. Thigpen AE, Davis DL, Gautier T, Imperato-McGinley J, Russell DW. 1992 Brief report: the molecular basis of steroid 5 -reductase deficiency in a large Dominican kindred. N Engl J Med. 327:1216–1219.[Medline]
10. Imperato-McGinley J, Gautier T, Zirinsky K, et al. 1992 Prostate visualization studies in males homozygous and heterozygous for 5 -reductase deficiency. J Clin Endocrinol Metab. 75:1022–1026.[Abstract]
11. Jenkins EP, Andersson S, Imperato-McGinley J, Wilson JD, Russell DW. 1992 Genetic and pharmacological evidence for more than one human steroid 5 -reductase. J Clin Invest. 89:293–300.
12. Harris G, Azzolina B, Baginsky W, et al. 1992 Identification and selective inhibition of an isozyme of steroid 5 -reductase in human scalp. Proc Natl Acad Sci USA. 89:10787–10791.[Abstract/Free Full Text]
13. Mellin TN, Busch RD, Rasmusson GH. 1993 Azasteroids as inhibitors of testosterone 5 -reductase in mammalian skin. J Steroid Biochem Mol Biol. 44:121–131.[CrossRef][Medline]
14. Thigpen AE, Silver RI, Guileyardo JM, Casey ML, McConnell JD, Russell DW. 1993 Tissue distribution and ontogeny of steroid 5 -reductase isozyme expression. J Clin Invest. 92:903–910.
15. Silver RI, Wiley EL, Davis DL, Thigpen AE, Russell DW, McConnell JD. 1994 Expression and regulation of steroid 5 -reductase 2 in prostate disease. J. Urol. 152:433–437.[CrossRef]
16. Luu-The V, Sugimoto Y, Puy L, et al. 1994 Characterization, expression, and immunohistochemical localization of 5 -reductase in human skin. J Invest Dermatol. 1994102 :221–226.
17. McConnell JD. 1995 Prostatic growth: new insights into hormonal regulation. Br J Urol. [Suppl 1] 76:5–10.
18. Ross RK, Bernstein L, Lobo RA, et al. 1992 5- reductase activity and risk of prostate cancer among Japanese and US white and black males. Lancet. 339:887–889.[CrossRef][Medline]
19. Ellsworth K, Harris G. 1995 Expression of the type 1 and 2 steroid 5- reductases in human fetal tissues. Biochem Biophys Res Commun. 215:774–780.[CrossRef][Medline]
20. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. 1951 Protein measurement with the Folin phenol reagent. J Biol Chem. 193:265–275.[Free Full Text]
21. Blanck A, Hansson T, Eriksson LC, Gustafsson JÅ. 1984 On mechanisms of sex differences in chemical carcinogenesis: effects on implantation of ectopic pituitary grafts on the early stages of liver carcinogenesis in the rat. Carcinogenesis. 5:1257–1262.[Abstract/Free Full Text]
22. Chomczynski P, Sacchi N. 1987 Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 62:156–159.[CrossRef]
23. Bjelfman C, Soderstrom TG, Brekkan E, et al. 1997 Differential gene expression of steroid 5 -reductase 2 in core needle biopsies from malignant and benign prostatic tissue. J Clin Endocrinol Metab. 82:2210–2214.[Abstract/Free Full Text]
24. Iehle C, Radvanyi F, Gil Diez de Medina S, et al. 1999 Differences in steroid 5 -reductase iso-enzymes expression between normal and pathological human prostate tissue. J Steroid Biochem Mol Biol. 68:189–195.[CrossRef][Medline]
25. McNeal JE. 1988 Normal histology of the prostate. Am J Surg Pathol. 12:619–633.[CrossRef][Medline]
26. Ross RK, Pike MC, Coetzee GA, et al. 1998 Androgen metabolism and prostate cancer: establishing a model of genetic susceptibility. Cancer Res. 58:4497–4504.[Abstract/Free Full Text]
27. Makridakis NM, Ross RK, Pike MC, et al. 1999 Association of mis-sense substitution in SRD5A2 gene with prostate cancer in African-American and Hispanic men in Los Angeles, USA. Lancet. 354:975–978.[CrossRef][Medline]

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