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. Issue 174 (November 2017)

• Record Type: Journal Article
• Authors: de Mello Martins, Antonio G. Gomes; Allegretta, Giuseppe; Unteregger, Gerhard; Haupenthal, Jörg; Eberhard, Jens; Hoffmann, Michael; van der Zee, Jill A.; Junker, Kerstin; Stöckle, Michael; Müller, Rolf; Hartmann, Rolf W.; Ohlmann, Carsten-H.
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 174(2017)
• Page Start: 183
• Page End: 191
• Publication Date: 2017-11
• Subjects: 5-pregnan-3, 6-diol-20-one -- 4-Abiraterone -- Neuroendocrine differentiation -- Castration-resistant prostate cancer -- CYP17A1 -- Neurosteroid -- Steroidogenesis; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2017.09.006
• Languages: English
• ISSNs: 0960-0760

Abstract

Graphical abstract: Highlights: Starved androgen-responsive prostate cancer cells produce 5α-pregnan-3β, 6α-diol-20-one. 5α-pregnan-3β, 6α-diol-20-one is a mitogenic product of pregnenolone metabolism. Abiraterone and D4A abolish pregnenolone metabolism in a CYP17A1-independent manner. Rise in DHEA levels hints at neuroendocrine differentiation. 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 Δ 4 -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.