Abstract
Intratumoural dihydrotestosterone (DHT) synthesis could be an explanation for castration resistance in prostate cancer (PC). By using liquid chromatography-mass spectrometry, we evaluated the intratumoral DHT synthesis from 5α-androstane-3β,17β-diol (3β-diol), which is inactive androgen metabolized from DHT. 3β-diol had biochemical potential to be converted to DHT via three metabolic pathways and could stimulate PC cell growth. Especially, 3β-diol was not only converted back to upstream androgens such as dehydroepiandrosterone (DHEA) or Δ5-androstenediol but also converted directly to DHT which is the main pathway from 3β-diol to DHT. Abiraterone had a significant influence on the metabolism of DHEA, epiandrosterone and 3β-diol, by the inhibition of the intratumoural 3β-hydroxysteroid dehydrogenase (3β-HSD) activities which is one of key catalysts in androgen metabolic pathway. The direct-conversion of 3β-diol to DHT was catalysed by 3β-HSD and abiraterone could inhibit this activity of 3β-HSD. These results suggest that PC had a mechanism of intratumoural androgen metabolism to return inactive androgen to active androgen and intratumoural DHT synthesis from 3β-diol is important as one of the mechanisms of castration resistance in PC. Additionally, the inhibition of intratumoural 3β-HSD activity could be a new approach to castration-resistant prostate cancer treatment.
Highlights
(A-dione) by the sequential hydroxylase and lyase activities of CYP17A1 in the adrenal gland
-diol, DHEA and EpiAND, we measured PSA secretions, absorbance of MTS assay and changes of DHT levels secreted into the medium by LNCaP cells by using liquid chromatography-mass spectrometry (LC-MS) (Fig. 2)
We presented three important findings: the identification of intratumoural DHT synthesis pathways from 3β-diol including direct-conversion of 3β-diol to DHT; back conversion of 3β-diol to upstream androgens and inhibition of the intratumoural 3β-hydroxysteroid dehydrogenase (3β-HSD)-mediated conversion by abiraterone
Summary
(A-dione) by the sequential hydroxylase and lyase activities of CYP17A1 in the adrenal gland Enzymes such as 3β-hydroxysteroid dehydrogenase (3β-HSD), 17β-hydroxysteroid dehydrogenase (17β-HSD) and steroid 5α-reductase (5α-SRD) participate in the intratumoural androgen metabolic pathway. DHEA, the most common precursor of T and DHT in PC tissue during ADT9–11, is taken up by PC cells and converted to DHT in the cytoplasm and this metabolism called as adrenal-androgen-axis. Our laboratory reported the other reformation pathway from 3β-diol to DHT via DHEA26 These studies suggest the existence of multiple DHT synthesis pathways from inactive androgens and could be a part of the mechanism behind castration resistance in PC. The enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD) is a key catalyst in androgen metabolism, converting DHEA to androstenedione (A-dione), Δ5-androstenediol (Δ5-Adiol) to T, EpiAND to 5α-A-dione and DHT to 3β-diol[27]. Data displayed are the mean ±s.d and are representative of at least three independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001, vs. CTRL, by using t-test
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
