PMID- 12604227
OWN - NLM
STAT- MEDLINE
DCOM- 20030512
LR  - 20190826
IS  - 0009-2797 (Print)
IS  - 0009-2797 (Linking)
VI  - 143-144
DP  - 2003 Feb 1
TI  - Role of human type 3 3alpha-hydroxysteroid dehydrogenase (AKR1C2) in androgen 
      metabolism of prostate cancer cells.
PG  - 401-9
AB  - Four human aldo-keto reductases (AKRs) that belong to the AKR1C subfamily 
      function in vitro as 3-keto-, 17-keto- and 20-ketosteroid reductases or as 
      3alpha-, 17beta- and 20alpha- hydroxysteroid oxidases to varying degrees. By 
      acting as ketosteroid reductases or hydroxysteroid oxidases these AKRs can either 
      convert potent sex hormones (androgens, estrogens and progestins) into their 
      inactive metabolites or they can form potent hormones by catalyzing the reverse 
      reaction. In this manner they may regulate occupancy and trans-activation of 
      steroid hormone receptors. Tissue distribution studies previously indicated that 
      AKR1C2 (type 3 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD)) and AKR1C3 (type 
      2 3alpha-HSD) are highly expressed in human prostate. An assessment of the 
      directionality of these AKR1C isozymes in a cellular environment would help 
      identify which isozymes are responsible for 5alpha-dihydrotestosterone 
      (5alpha-DHT) formation or its elimination in the prostate. An imbalance in 
      5alpha-DHT levels has been implicated in development of prostate carcinoma and 
      benign prostatic hyperplasia. We focused our attention on AKR1C2 since this is 
      the isoform that will oxidize 3alpha-androstanediol (3alpha-diol) to 5alpha-DHT 
      in vitro, suggesting it could elevate 5alpha-DHT levels. To determine whether 
      AKR1C2 preferentially functions as a reductase or an oxidase in a cellular 
      context, we transiently transfected AKR1C2 (pcDNA3-AKR1C2) into COS-1 cells and 
      stably transfected pcDNA3-AKR1C2 and pLNCX-AKR1C2 constructs into PC-3 and LNCaP 
      cells, respectively. COS-1 is a monkey kidney cell line, while PC-3 and LNCaP 
      cells are androgen receptor (-) and (+) prostate adenocarcinoma cell lines, 
      respectively. In transient COS-1-AKR1C2 and in stable PC3-AKR1C2 transfectants, 
      AKR1C2 functioned as a 3-ketosteroid reductase inactivating 5alpha-DHT. In 
      androgen dependent human prostate cancer cells LNCaP, it was not possible to 
      ascertain the preferred direction of AKR1C2 by stable transfection due to the 
      high rate of 5alpha-DHT and 3alpha-diol glucuronidation. Based on these findings 
      AKR1C2 may diminish 5alpha-DHT and prevent this ligand from activating the 
      androgen receptor in situ.
FAU - Rizner, Tea Lanisnik
AU  - Rizner TL
AD  - Department of Pharmacology, University of Pennsylvania, School of Medicine, 3620 
      Hamilton Walk, Philadelphia, PA 19104-6084, USA.
FAU - Lin, Hsueh K
AU  - Lin HK
FAU - Penning, Trevor M
AU  - Penning TM
LA  - eng
GR  - CA90744/CA/NCI NIH HHS/United States
GR  - DK47015/DK/NIDDK NIH HHS/United States
GR  - DK54925/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - Ireland
TA  - Chem Biol Interact
JT  - Chemico-biological interactions
JID - 0227276
RN  - 0 (Androgens)
RN  - EC 1.1.- (Hydroxysteroid Dehydrogenases)
RN  - EC 1.1.1.357 (AKR1C2 protein, human)
SB  - IM
MH  - Androgens/*metabolism
MH  - Animals
MH  - COS Cells
MH  - Humans
MH  - Hydroxysteroid Dehydrogenases/*metabolism
MH  - Male
MH  - Prostatic Neoplasms/enzymology/*metabolism/pathology
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Tumor Cells, Cultured
EDAT- 2003/02/27 04:00
MHDA- 2003/05/13 05:00
CRDT- 2003/02/27 04:00
PHST- 2003/02/27 04:00 [pubmed]
PHST- 2003/05/13 05:00 [medline]
PHST- 2003/02/27 04:00 [entrez]
AID - S0009279702001795 [pii]
AID - 10.1016/s0009-2797(02)00179-5 [doi]
PST - ppublish
SO  - Chem Biol Interact. 2003 Feb 1;143-144:401-9. doi: 10.1016/s0009-2797(02)00179-5.