Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer

Abstract

Androgen deprivation therapy is the frontline treatment for metastatic prostate cancer; however, because the majority of cases of advanced prostate cancer progress to castration-resistant prostate cancer (CRPC), there is a considerable need to better understand the synthesis of intratumoral concentrations of the androgen receptor (AR) agonist, 5α-dihydrotestosterone (DHT) in CRPC. In a recent article in the Proceedings of the National Academy of Sciences, Chang et al. show that, contrary to widely held assumptions, the dominant pathway to DHT synthesis does not involve testosterone as a precursor to DHT, but instead involves the conversion of Δ⁴-androstenedione (AD) to 5α-dione (AD→5α-dione→DHT) by the steroid-5α-reductase isoenzyme 1 (SRD5A1). The authors show that it is this alternative pathway that drives the progression of CRPC, and they confirm these findings in six established human prostate cancer cell lines as well as in the metastatic tumors from two patients with CRPC. Such findings open the door to new areas of research and to the development of new therapeutic targets in CRPC.

Keywords: :

• 5α-dione
• DHEA
• DHT
• SRD5A1
• prostate cancer
• testosterone
• Δ⁴-androstenedione

Androgen deprivation therapy is the standard treatment for advanced prostate cancer and in most cases initially effective; however, the majority of patients eventually progress to a state of castration-resistant prostate cancer (CRPC).1 Previous clinical studies have shown that intratumoral concentrations of testosterone and the more potent androgen receptor (AR) agonist, 5α-dihydrotestosterone (DHT) are maintained in CRPC.2,3 In the context of CRPC, the adrenal steroid dehydroepiandrosterone (DHEA) and its sulfated form are converted to Δ4-androstenedione (AD), which can be further reduced to testosterone and DHT (DHEA→AD→T→DHT).4 This pathway has been generally accepted as the main pathway responsible for maintaining testosterone and DHT levels in CRPC.5 Because the majority of cases of metastatic prostate cancer progress to CRPC, there is a considerable need to understand the mechanism behind this progression in order to effectively find therapeutic targets.

The study by Chang et al. published in the Proceedings of the National Academy of Sciences, shows that the dominant pathway to DHT synthesis from adrenal precursors bypasses testosterone synthesis to drive CRPC.6 AD can be reduced to either testosterone or 5α-dione, both of which can be further reduced to DHT.4 Here, the authors show that in six established human prostate cancer cell lines, the synthesis of 5α-dione from AD occurs earlier and more rapidly than the synthesis of testosterone from AD, demonstrating that this alternative pathway is the dominant route to DHT synthesis. These findings were confirmed in the metastatic tumors of two patients with CRPC. The authors then examined whether it is this alternative pathway that drives the progression to CRPC. Using subcutaneous xenograft studies with LAPC4 and LNCaP models in surgically castrated mice supplemented with testosterone and AD, they found that tumors in mice supplemented with AD had significantly more rapid growth than tumors supplemented with testosterone. These findings reveal that this alternative pathway is responsible for intratumoral synthesis of DHT, and it also drives the progression of CRPC.

Previous studies have shown that steroid 5α-reductase isoenzyme-1 (SRD5A1) expression is increased, while SRD5A2 expression is decreased in the progression to CRPC, and it has been previously thought that SRD5A1 expression is increased to catalyze the conversion of testosterone to DHT.7,8 Chang et al. however, found that AD is a better substrate for this isoenzyme than testosterone. Additionally, they demonstrate that silencing SRD5A1 expression blocks both 5α-dione and DHT synthesis, suggesting SRD5A1 is required in the flux from AD to 5α-dione. Furthermore, silencing SRD5A1 expression not only blocks the flux from AD to 5α-dione but also causes an increase in the flux from AD to testosterone, thus showing that the flux from AD to testosterone occurs only when the conversion of AD to 5α-dione is blocked.

To assess the role of decreased SRD5A1 expression in the progression of CRPC, the authors used surgically orchiectomized mice with silenced SRD5A1 expression and supplemented with sustained-release AD. They found that silenced SRD5A1 expression caused a significant decrease in tumor progression. Furthermore, they found SRD5A1 expression increased over time, suggesting a selection for cells with higher SRD5A1 expression and demonstrating the true requirement for the role of SRD5A1 in the progression of CRPC.

Although there are more studies that need to be done before these findings can be translated into potential therapeutic agents, Chang et al. provide considerable insight into the major pathway responsible for DHT synthesis from adrenal precursors in CRPC. Contrary to what has previously been thought, the dominant pathway driving CRPC does not involve the synthesis of testosterone, but instead uses the conversion of AD to 5α-dione by SRD5A1 to produce intratumoral concentrations of DHT (AD→5α-dione→DHT). These findings suggest that therapeutic targets that aim to block the conversion of AD to testosterone may not be as effective at inhibiting DHT synthesis as those that target this alternative pathway involving the conversion of AD to 5α-dione. These findings open the door to the development of new therapeutic targets in CRPC.

Abbreviations

CRPC	=	castration-resistant prostate cancer
DHT	=	5α-dihydrotestosterone
AD	=	Δ4-androstenedione
SRD5A1	=	steroid-5α-reductase isoenzyme 1
AR	=	androgen receptor
DHEA	=	dehydroepiandrosterone