2. Academic Validation
  3. CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone

CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone

  • J Steroid Biochem Mol Biol. 2017 Nov;174:183-191. doi: 10.1016/j.jsbmb.2017.09.006.
Antonio G Gomes de Mello Martins 1,  Giuseppe Allegretta 1,  Gerhard Unteregger 2,  Jörg Haupenthal 1,  Jens Eberhard 1,  Michael Hoffmann 3,  Jill A van der Zee 2,  Kerstin Junker 2,  Michael Stöckle 2,  Rolf Müller 3,  Rolf W Hartmann 4,  Carsten-H Ohlmann 5
Affiliations

Affiliations

  • 1 Department of Drug Design and Optimization (DDOP), Helmholtz Institute for Pharmaceutical Research Saarland, Campus E8.1, 66123 Saarbrücken, Germany.
  • 2 Saarland University, Department of Urology and Pediatric Urology, 66424 Homburg/Saar, Germany.
  • 3 Department of Microbial Natural Products (MINS), Helmholtz Institute for Pharmaceutical Research Saarland, Campus E8.1, 66123 Saarbrücken, Germany.
  • 4 Department of Drug Design and Optimization (DDOP), Helmholtz Institute for Pharmaceutical Research Saarland, Campus E8.1, 66123 Saarbrücken, Germany; Department of Pharmaceutical and Medicinal Chemistry, Saarland University, 66123 Saarbrücken, Germany. Electronic address: [email protected].
  • 5 Saarland University, Department of Urology and Pediatric Urology, 66424 Homburg/Saar, Germany. Electronic address: [email protected].
PMID: 28890368 DOI: 10.1016/j.jsbmb.2017.09.006
Abstract

CYP17A1-independent intratumoral steroid hormone synthesis is regarded as one possible explanation for resistance to treatment with the CYP17-inhibitor Abiraterone (Abi). The aim of our study was therefore to investigate the steroid metabolism of prostate Cancer cells under serum starvation and the effects of Abi treatment. We assessed steroid metabolism in a panel of prostate Cancer cells under serum starvation by radioactivity detector-coupled HPLC and HPLC-ESI-ToF-mass spectrometry after treatment with pregnenolone, progesterone and allopregnanolone. We further evaluated the effects of Abi on steroid metabolism of testosterone, dihydrotestosterone (DHT) and dehydroepiandrosterone (DHEA) by Enzyme immunoassays (EIAs). Androgen-responsive cell lines metabolized pregnenolone primarily to mitogenic steroid 5α-pregnan-3β,6α-diol-20-one under serum starvation. Co-administration of Abi lead to detectable concentrations of the Abi metabolite Δ4-Abi (D4A), known to inhibit enzymes other than CYP17A1 in steroid metabolism. In addition, co-administration of Abi abrogated pregnenolone metabolism and resulted in a CYP17A1-independent significant increase of DHEA (13- to >100-fold) and DHT (2.5-fold) in androgen-responsive cells. Our results demonstrate the CYP17A1-independent formation of 5α-pregnan-3β,6α-diol-20-one by androgen-responsive prostate Cancer cells under serum starvation and its inhibition by Abi. Its metabolism from pregnenolone suggests a major steroidogenesis shift in these cells, hinting at a neuroendocrine transdifferentiation phenomenon. The marked increase of DHEA levels by Abi resembles the steroidogenic pathways in nervous tissue, in a manner that precludes CYP17A1 activity. To which extent these processes are responsible or involved in the development of resistance to Abi, needs to be further elucidated.

Keywords

4-Abiraterone; 5-pregnan-3,6-diol-20-one; CYP17A1; Castration-resistant prostate cancer; Neuroendocrine differentiation; Neurosteroid; Steroidogenesis.

Figures
Products