HUMAN PROSTATIC 3A HYDROXYSTEROID DEHYDROGENASE

Summary

Principal Investigator: Hsueh Kung Lin
Abstract: DESCRIPTION (Adapted from the Applicant's Abstract): In androgen target tissues 3a-hydroxysteroid dehydrogenases (3a-HSDs) may regulate the occupancy of androgen receptor (AR) by interconverting 5a-dihydrotestosterone (5a-DHT, a potent androgen) with 5a-androstane-3a,17b-diol (3a-diol, a weak androgen). We have obtained type 2 and type 3 3a-HSD cDNAs expressed in human prostate and overexpressed the enzymes in E. coli. Kinetic studies of these recombinant enzymes show that type 3 3a-HSD functions as both a 3a-and 17b-HSD to inactivate active androgens, whereas, type 3 3a-HSD interconverts 5a-DHT with 3a- diol. Levels of 3a-HSD mRNA were higher in primary cultures of prostatic epithelial cells than stromal cells; and elevated levels of 3a-HSD mRNA were observed in primary cultures of epithelial cells derived from benign prostatic hyperplasia and prostatic carcinoma tissues. Expression of steady state levels of 3a-HSD mRNA is up-regulated by epidermal growth (EGF) in human prostatic cell lines, LNCaP (androgen sensitive) and PC3 (androgen insensitive). The focus of this proposal is to examine the physiological functions of type 2 and type 3 3a-HSD in regulating androgen metabolism and their activities in modulating prostatic cell proliferation will be investigated. This will be accomplished by stably transfecting type 2 and type 3 3a-HSD cDNAs into these cells. Second, levels of endogenous type 2 and type 3 3a-HSD transcripts will be examined in RNA extracted from the cell lines and normal prostate using ribonuclease protection assay (RPA). Third, EGF-regulated type 2 and type 3 3a-HSD mRNA levels will be examined using RPA. Changes in 3a-HSD expression mediated by EGF will be examined in cell lysates by immunotitration of the enzyme activity. Fourth, to understand the constitutive and EGF- regulated type 2 and type 3 3a-HSD expression in prostatic cells, the 5'-flanking regions of the 3a-HSD genes will be sequenced and cis-acting elements responsible for transcription regulation of two isoforms will be identified.
Funding Period: 1998-09-28 - 2005-07-31
more information: NIH RePORT

Top Publications

  1. ncbi Aldo-keto reductase (AKR) 1C3: role in prostate disease and the development of specific inhibitors
    Trevor M Penning
    Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104 6084, USA
    Mol Cell Endocrinol 248:182-91. 2006
  2. ncbi Increased expression of type 2 3alpha-hydroxysteroid dehydrogenase/type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma
    K M Fung
    Department of Urology, University of Oklahoma Health Sciences Center, 920 Stanton L Young Blvd, WP3150, Oklahoma City, OK 73104, USA
    Endocr Relat Cancer 13:169-80. 2006

Scientific Experts

  • TREVOR PENNING
  • K M Fung
  • E N S Samara
  • J T Yang
  • A Metwalli
  • C Z Liu
  • C Wong
  • J V Pitha
  • D J Culkin
  • B P Kropp
  • Hsueh Kung Lin
  • B Bane
  • R Krlin

Detail Information

Publications2

  1. ncbi Aldo-keto reductase (AKR) 1C3: role in prostate disease and the development of specific inhibitors
    Trevor M Penning
    Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104 6084, USA
    Mol Cell Endocrinol 248:182-91. 2006
    ..These compounds can now be used to determine the role of AKR1C3 in producing two proliferative signals in the prostate namely testosterone and 9alpha,11beta-PGF2...
  2. ncbi Increased expression of type 2 3alpha-hydroxysteroid dehydrogenase/type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma
    K M Fung
    Department of Urology, University of Oklahoma Health Sciences Center, 920 Stanton L Young Blvd, WP3150, Oklahoma City, OK 73104, USA
    Endocr Relat Cancer 13:169-80. 2006
    ..Although the biological significance of elevated AKR1C3 in prostatic carcinoma is uncertain, AKR1C3 may be responsible for the trophic effects of androgens and/or PGs on prostatic epithelial cells...