BERKELEY, CA (UroToday.com) - In the February 15, 2011 issue of Cancer Research, Dr. James Mohler and collaborators report on intracrine androgen biosynthesis as a mechanism for castration-resistant prostate cancer (CRPC) progression.
Even with castrate levels of circulating testosterone, the androgen receptor (AR) is activated by other mechanisms to include amplification, mutation, ligand independent activation, and activation by androgens produced within CRPC cells. Within CRPC cells, biosynthetic enzymes that generate DHT from precursors are upregulated and result in “intracrine androgen” production. This study investigated whether AR activation by the conversion of androstanediol to DHT facilitates to CaP growth in the face of low levels of circulating testicular androgen levels. Androstenedione and dehydroepiandrosterone are circulating adrenal androgens converted to androstanediol and DHT in the prostate. Androstanediol is an inactive DHT metabolite that can be oxidized to DHT, a reversible reaction.
Prostate specimens used in the study included benign prostate (AS-BP), androgen-stimulated and CRPC tissues. In cell lines treated with testosterone, DHT or androstanediol, a dose-dependent increase in AR transcription was noted with testosterone and DHT. However, stimulation with androstanediol only conferred AR transactivation in certain cell lines, suggesting the low affinity of androstanediol for AR and subsequent conversion to DHT was cell-specific. Further studies demonstrated the cell-specific AR transcriptional activity and CaP cell growth with exposure to androstanediol resulted from oxidative metabolism of androstanediol to DHT. Quantitative RT-PCR analysis of RNA from different cell types indicated higher levels of the enzyme 17β-HSD6 in prostate-derived cells. This correlated with AR transactivation and DHT levels after incubation with androstanediol. In CaP cell lines, AR transactivation with androstanediol was comparable to testosterone and DHT. The greater mRNA levels correlated with greater 17β-HSD6 protein levels. Biosynthetic enzyme levels were measured in the CWR22 xenograft at different time points after castration. The CWR22 xenograft regresses after castration and then regrows over a 6-month period. 17β-HSD6 levels dropped 5-fold, starting 2 days after castration and remained low during tumor regrowth. In vivo intracrine metabolism of androstanediol to DHT was evaluated by injecting CWR22 tumors in mice with 1mg androstanediol. Tumors had 28-fold greater Intratumoral DHT measured by mass spec compared to tumors injected with a control vehicle. These experiments demonstrate that the conversion of androstanediol to DHT is active in prostate cancer tissues to stimulate AR transactivation.
Mohler JL, Titus MA, Bai S, Kennerley BJ, Lih FB, Tomer KB, Wilson EM
Cancer Res. 2011 Feb 15;71(4):1486-96