Clarifying the mechanisms underlying prostate cancer (PC) progression and resistance to androgen deprivation therapy (ADT) is an urgent clinical issue. ADT influences steroidal metabolism in patients with PC and promotes the accumulation of carbon 21 steroids (C21s), such as progestin. Because the enzymes responsible for C21s metabolism are similar to those for androgen metabolism, PC cells may be able to metabolize C21s intracellularly. Therefore, there is a possibility that intracrine C21s are implicated in PC progression and resistance to ADT, and the influence of C21s on PC cells is yet to be elucidated. In the present study, we focused on 20β-hydroxy-5α-dihydroprogesterone (20β-OHDHP), a C21s metabolized from progestin, and showed that 20β-OHDHP is synthesized in PC cells and is able to directly stimulate the androgen receptor (AR).
LNCaP, VCaP, and DU145 cells, which express a mutant AR (mAR), wild-type AR (wAR), and glucocorticoid receptor (GR), respectively, were incubated in the presence of several agents. After incubation, cell growth was determined by the MTS assay. PSA levels were determined by an enzyme immunoassay, and C21s and androgen levels were measured using liquid chromatography-mass spectrometry. Gene expression was analyzed by quantitative real-time polymerase chain reaction, and steroidal-receptor-related signaling was determined by a reporter assay.
We affirmed that 20β-OHDHP was synthesized from pregnenolone intracellularly in LNCaP and VCaP cells, and 20β-OHDHP significantly promoted the growth of both cell lines without androgen conversion. 20β-OHDHP directly stimulated both mAR and wAR. The presence of 20β-OHDHP was sufficient for the proliferation and survival of LNCaP or VCaP cells, and 20β-OHDHP promoted cell growth even in the presence of abiraterone. Using DU145 cells, we affirmed that 20β-OHDHP did not stimulate GR, which has a potential to bypass AR signaling in PC cells promote PC cell growth.
Under ADT, 20β-OHDHP synthesized intracellularly from accumulated progestin in PC cells may accelerate cell growth via stimulation of both wAR and mAR. This pathway may represent an interesting candidate for targeted therapy.
The Prostate. 2017 Dec 01 [Epub ahead of print]
Takashi Ando, Tsutomu Nishiyama, Itsuhiro Takizawa, Yoshimichi Miyashiro, Noboru Hara, Yoshihiko Tomita
Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata, Japan., ASKA Pharmaceutical Medical Co. Ltd., Kawasaki, Kanagawa, Japan.