PMID- 37321973
OWN - NLM
STAT- MEDLINE
DCOM- 20240221
LR  - 20240221
IS  - 1097-0045 (Electronic)
IS  - 0270-4137 (Linking)
VI  - 83
IP  - 13
DP  - 2023 Sep
TI  - 3betaHSD activity saturates at physiological substrate concentrations in intact 
      cells.
PG  - 1306-1309
LID - 10.1002/pros.24587 [doi]
AB  - BACKGROUND: Conversion of adrenally produced dehydroepiandrosterone (DHEA) to the 
      potent androgen dihydrotestosterone (DHT) is an important mechanism by which 
      prostate cancer reaches castration resistance. At the start of this pathway is a 
      branch point at which DHEA can be converted to Delta(4) -androstenedione by the 
      enzyme 3beta-hydroxysteroid dehydrogenase (3betaHSD) or to Delta(5) -androstenediol by 
      17betaHSD. To better understand this process, we studied the kinetics of these 
      reactions in cells. METHODS: Prostate cancer cells (LNCaP cell line) were 
      incubated with steroids (DHEA and Delta(5) -androstenediol) over a range of 
      concentrations and the steroid metabolism reaction products were measured by mass 
      spectrometry or by high-performance liquid chromatography to determine reaction 
      kinetics. To confirm the generalizability of results, experiments were also 
      performed in JEG-3 placental choriocarcinoma cells. RESULTS: The two reactions 
      displayed very different saturation profiles, with only the 3betaHSD-catalyzed 
      reaction beginning to saturate within a physiological substrate concentration 
      range. Strikingly, incubating LNCaP cells with low (in the ~10 nM range) 
      concentrations of DHEA resulted in a large majority of the DHEA undergoing 
      3betaHSD-catalyzed conversion to Delta(4) -androstenedione, whereas high concentrations 
      of DHEA (in the 100s of nM range) resulted in most of the DHEA undergoing 
      17betaHSD-catalyzed conversion to Delta(5) -androstenediol. CONCLUSION: Contrary to 
      expectations from previous studies that used purified enzyme, cellular metabolism 
      of DHEA by 3betaHSD begins to saturate in the physiological concentration range, 
      suggesting that fluctuations in DHEA concentrations could be buffered at the 
      downstream active androgen level.
CI  - (c) 2023 The Authors. The Prostate published by Wiley Periodicals LLC.
FAU - McManus, Jeffrey M
AU  - McManus JM
AD  - Genitourinary Malignancies Research Center, Department of Cancer Biology, Lerner 
      Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
FAU - Chung, Yoon-Mi
AU  - Chung YM
AD  - Genitourinary Malignancies Research Center, Department of Cancer Biology, Lerner 
      Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
FAU - Sharifi, Nima
AU  - Sharifi N
AUID- ORCID: 0000-0003-1281-3474
AD  - Genitourinary Malignancies Research Center, Department of Cancer Biology, Lerner 
      Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
AD  - Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland 
      Clinic, Cleveland, Ohio, USA.
AD  - Department of Urology, Glickman Urological and Kidney Institute, Cleveland 
      Clinic, Cleveland, Ohio, USA.
AD  - Desai Sethi Urology Institute, University of Miami Miller School of Medicine, 
      Miami, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20230615
PL  - United States
TA  - Prostate
JT  - The Prostate
JID - 8101368
RN  - 0 (Androgens)
RN  - 0 (Androstenediols)
RN  - 409J2J96VR (Androstenedione)
RN  - 459AG36T1B (Dehydroepiandrosterone)
SB  - IM
MH  - Humans
MH  - Male
MH  - *Androgens
MH  - Androstenediols
MH  - Androstenedione/metabolism
MH  - Cell Line, Tumor
MH  - Dehydroepiandrosterone/metabolism
MH  - *Prostatic Neoplasms/pathology
OTO - NOTNLM
OT  - androgens
OT  - enzyme kinetics
OT  - prostate cancer
EDAT- 2023/06/16 01:08
MHDA- 2023/08/18 06:42
CRDT- 2023/06/15 22:33
PHST- 2023/05/09 00:00 [revised]
PHST- 2023/03/29 00:00 [received]
PHST- 2023/06/05 00:00 [accepted]
PHST- 2023/08/18 06:42 [medline]
PHST- 2023/06/16 01:08 [pubmed]
PHST- 2023/06/15 22:33 [entrez]
AID - 10.1002/pros.24587 [doi]
PST - ppublish
SO  - Prostate. 2023 Sep;83(13):1306-1309. doi: 10.1002/pros.24587. Epub 2023 Jun 15.