Activation of the Androgen Receptor by Intratumoral Bioconversion of Androstanediol to Dihydrotestosterone in Prostate Cancer

Abstract

The androgen receptor (AR) mediates the growth of benign and malignant prostate in response to dihydrotestosterone (DHT). In patients undergoing androgen deprivation therapy for prostate cancer, AR drives prostate cancer growth despite low circulating levels of testicular androgen and normal levels of adrenal androgen. In this report, we demonstrate the extent of AR transactivation in the presence of 5a-androstane-3a,17b-diol (androstanediol) in prostate-derived cell lines parallels the bioconversion of androstanediol to DHT. AR transactivation in the presence of androstanediol in prostate cancer cell lines correlated mainly with mRNA and protein levels of 17b-hydroxysteroid dehydrogenase 6 (17b-HSD6), one of several enzymes required for the interconversion of androstanediol to DHT and the inactive metabolite androsterone. Levels of retinol dehydrogenase 5, and dehydrogenase/reductase short-chain dehydrogenase/reductase family member 9, which also convert androstanediol to DHT, were lower than 17b-HSD6 in prostate-derived cell lines and higher in the castration-recurrent human prostate cancer xenograft. Measurements of tissue androstanediol using mass spectrometry demonstrated androstanediol metabolism to DHT and androsterone. Administration of androstanediol dipropionate to castration-recurrent CWR22R tumor-bearing athymic castrated male mice produced a 28-fold increase in intratumoral DHT levels. AR transactivation in prostate cancer cells in the presence of androstanediol resulted from the cell-specific conversion of androstanediol to DHT, and androstanediol increased LAPC-4 cell growth. The ability to convert androstanediol to DHT provides a mechanism for optimal utilization of androgen precursors and catabolites for DHT synthesis.

Steroidogenic Enzyme AKR1C3 Is a Novel Androgen Receptor-Selective Coactivator that Promotes Prostate Cancer Growth

“…Interestingly, animal models have indicated that resistance to abiraterone treatment may be due to increase in the expression of its target, Cyp17A1, as well as higher expression of AR and AKR1C3 (8). Moreover, the back door pathways (29)(30)(31) to synthesize DHT (Fig. 1A, filled arrows) despite treatment with abiraterone (29) require 17b-HSDs for biosynthesis of potent androgens.…”

331 Androgen Deprivation Promotes Intratumoral Synthesis of Dihydrotestosterone From Androgen Metabolites in Prostate Cancer

“…Rabbit polyclonal antibody for HSD17B4 was obtained from GeneTex (Irvine, CA, USA), and rabbit polyclonal antibody for HSD17B6 was obtained from Abcam (Cambridge, MA, USA) 41,42 . Both anti-HSD17B4 and HSD17B6 antibodies were used for immunohistochemistry at 8 mg/ml.…”

The mouse as a model to investigate sex steroid metabolism in the normal and pathological prostate

“…Because of this discrepancy biochemical function rather than structural similarity may be a worthwhile point to consider when extrapolating the significance of 17␤HSD subtypes between mouse and man. Recently, the increased 17␤HSD6 expression in prostate cancer was associated with the activation of back door pathway of steroid synthesis [217] and decreased 17␤HSD2 and increased 17␤HSD3 [218] expression was observed in prostate cancer specimens. However, these pathways are not yet characterised in murine PCa models.…”