Abstract 960: Intratumoral dihydrotestosterone regulation by conversion of androstanediol to dihydrotestosterone in prostate cancer

Abstract

Abstract Purpose It has become apparent that resurgent androgen receptor activity in castration-resistant prostate cancer can be accounted for in part through intratumoral androgen synthesis. The potent androgen dihydrotestosterone (DHT) yields an inactive androgen 5α-androstane-3α17α-diol (androstanediol/3α-diol) in the prostate. The metabolism of 3α-diol and relationships among other androgens have not been elucidated. Therefore, we studied the metabolism of 3α-diol in prostate cancer cells, as well as the expression of 17α-hydroxysteroid dehydrogenase 6 (17α-HSD6), a key enzyme of oxidative 3α-HSD that converts 3α-diol into DHT, in prostate cancer cells and tissues using real time-PCR and immunohistochemistry. Finally, we studied the correlation between serum 3α-diol G levels and androgens in localized prostate cancer patients. Methods LNCaP and VCaP cells were cultured in the hormone-depleted medium with presence/absence of 3α-diol, and the intracellular levels of androstenedione, testosterone and DHT were concurrently determined by liquid chromatography tandem mass spectrometry. LNCaP and VCaP cells were exposed to 3α-diol and bicalutamide in various concentrations. Prostate-specific antigen (PSA) levels in media were assayed. To examine the long term effect of androgen deprivation, LNCaP was cultured in hormone-depleted medium with 1nM DHEA. Transcriptome expression was analyzed to detect expression levels of 17α-HSD6. Expression scores for 17α-HSD6 in radical prostatectomy specimens treated with or without androgen deprivation therapy (ADT) were evaluated using immunohistochemistry. Seventy-two patients with localized prostate cancer patients were prospectively studied based on blood samples before and after ADT for 6 months. Results DHT was synthesized from 3α-diol in prostate cancer cells. Prostate cancer cells produced PSA in a dose-dependent manner with 3α-diol. Prostate cancer cells pretreated with 3α-diol showed a dose-dependent decrease in PSA production with bicalutamide. In the lower passages LNCaP cells treated with DHEA, expression of 17α-HSD6 showed much less striking change. However, in the higher passage LNCaP cells, 17α-HSD6 was up-regulated. The score for 17α-HSD6 in prostate cancer tissues treated with ADT was significantly higher than that without ADT (p<0.001). There were significant positive relationships between serum DHEA-S and 3α-diol G levels before and after ADT. Conclusion We verified the synthesis of DHT from 3α-diol in prostate cancer cells in this study and elucidated that the serum 3α-diol G level well reflects the adrenal androgen milieu in localized prostate cancer patients. Therefore, 3α-diol can be a potential precursor of the most active androgen DHT in prostate cancer. Our data suggest that the adrenal androgen-DHT axis can be a potential therapeutic target for treating prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 960. doi:1538-7445.AM2012-960