Article

5α-reductase type 3 enzyme in benign and malignant prostate

Department of Urology, Roswell Park Cancer Institute, Buffalo, New York.
The Prostate (Impact Factor: 3.57). 02/2014; 74(3). DOI: 10.1002/pros.22745
Source: PubMed

ABSTRACT Currently available 5α-reductase inhibitors are not completely effective for treatment of benign prostate enlargement, prevention of prostate cancer (CaP), or treatment of advanced castration-recurrent (CR) CaP. We tested the hypothesis that a novel 5α-reductase, 5α-reductase-3, contributes to residual androgen metabolism, especially in CR-CaP.
A new protein with potential 5α-reducing activity was expressed in CHO-K1 cellsandTOP10 E. coli for characterization. Protein lysates and total mRNA were isolated from preclinical and clinical tissues. Androgen metabolism was assessed using androgen precursors and thin layer chromatography or liquid chromatography tandem mass spectrometry.
The relative mRNA expression for the three 5α-reductase enzymes in clinical samples of CR-CaP was 5α-reductase-3 ≫ 5α-reductase-1 > 5α-reductase-2. Recombinant 5α-reductase-3 protein incubations converted testosterone, 4-androstene-3,17-dione (androstenedione) and 4-pregnene-3,20-dione (progesterone) to dihydrotestosterone, 5α-androstan-3,17-dione, and 5α-pregnan-3,20-dione, respectively. 5α-Reduced androgen metabolites were measurable in lysates from androgen-stimulated (AS) CWR22 and CR-CWR22 tumors and clinical specimens of AS-CaP and CR-CaP pre-incubated with dutasteride (a bi-specific inhibitor of 5α-reductase-1 and 2).
Human prostate tissues contain a third 5α-reductase that was inhibited poorly by dutasteride at high androgen substrate concentration in vitro, and it may promote DHT formation in vivo, through alternative androgen metabolism pathways when testosterone levels are low. Prostate © 2013 Wiley Periodicals, Inc.

Download full-text

Full-text

Available from: Mark Titus, Feb 21, 2014
2 Followers
 · 
79 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Underage drinking is a leading public health problem in developed countries. An increasing proportion of adolescents consume alcoholic beverages every weekend. Increased anxiety, irritability, and depression among adolescents may induce them to seek for the anxiolytic and rewarding properties of alcohol. Allopregnanolone (AlloP) shares rewarding effects of ethanol and modulates ethanol intake. The rate-limiting enzyme in the biosynthesis of AlloP is steroid 5α-reductase (5α-R), which is expressed as three isozymes, 5α-R1, 5α-R2, and 5α-R3. The objective of this study was to quantify the expression levels of 5α-R isozymes in prefrontal cortex (PFC) of adolescent male rats after three different regimes of ethanol administration. Adolescent male Wistar rats were administered with ethanol (4 g/kg) or saline intraperitoneally for 1 day (acute), for 7 days (chronic), or every 72 h for 14 days (chronic intermittent). Messenger (m)RNA and protein levels of 5α-R isozymes were measured by quantitative RT-PCR and Western blot, respectively. Ethanol significantly increased mRNA and protein levels of 5α-R1, 5α-R2, and 5α-R3 in the three different regimes of ethanol administration, being higher in the chronic intermittent regime in comparison with the others. The expression of the AlloP-biosynthetic enzyme 5α-Rs increases in the prefrontal cortex of adolescent male rats under acute, chronic, and chronic intermittent regime of ethanol administration. The latter is very interesting because it mimics the teenage drinking behavior.
    Psychopharmacology 04/2014; 231(17). DOI:10.1007/s00213-014-3558-6 · 3.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Prostate cancer is the second leading cause of cancer death in adult males in the United States. Recent advances have found that the fatal form of this cancer known as castration resistant prostate cancer (CRPC) remains hormonally driven despite castrate levels of circulating androgens. CRPC arises since the tumor undergoes adaptation to low levels of androgens by either synthesizing its own androgens (intratumoral androgens) or by alterations in the androgen receptor (AR). This article reviews the major routes to testosterone and dihydrotestosterone in CRPC, examines the enzyme targets and progress in the development of isoform specific inhibitors that could block intratumoral androgen biosynthesis. Because redundancy exists in these pathways it is likely that inhibition of a single pathway will lead to up-regulation of another so that drug resistance would be anticipated. Drugs that target multiple pathways or agents that block intratumoral androgen biosynthesis and antagonize the AR offer the most promise. Optimal use of enzyme inhibitors or AR antagonists to ensure maximal benefit to CRPC patients will also require application of precision molecular medicine to determine that a tumor in a particular patient will be responsive to these treatments either alone or in combination.
    Endocrine Related Cancer 05/2014; 21(4). DOI:10.1530/ERC-14-0109 · 4.91 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Development of castration-resistant prostate cancer (CRPC) in a low androgen environment, arising from androgen deprivation therapy (ADT), is a major problem in patients with advanced prostate cancer (PCa). Several mechanisms have been hypothesized to explain the progression of PCa to CRPC during ADT, one of them is so called persistent intratumoral steroidogenesis. The existence of intratumoral steroidogenesis was hinted based on the residual levels of intraprostatic testosterone (T) and dihydrotestosterone (DHT) after ADT. Accumulating evidence has shown that the intraprostatic androgen levels after ADT are sufficient to induce cancer progression. Several studies now have demonstrated that PCa cells are able to produce T and DHT from different androgen precursors, such as cholesterol and the adrenal androgen, dehydroepiandrosterone (DHEA). Furthermore, up-regulation of genes encoding key steroidogenic enzymes in PCa cells seems to be an indicator for active intratumoral steroidogenesis in CRPC cells. Currently, several drugs are being developed targeting those steroidogenic enzymes, some of which are now in clinical trials or are being used as standard care for CRPC patients. In the future, novel agents that target steroidogenesis may add to the arsenal of drugs for CRPC therapy.
    09/2014; 2(3):105-13. DOI:10.12954/PI.14063