The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer

Abstract

The survival and progression of prostate cancer are generally dependent on expression of the androgen receptor (AR), as well as the availability of endogenous AR agonists. Originating from the gonads, testosterone is released into circulation and is converted by steroid-5α-reductase in prostate cancer to 5α-dihydrotestosterone (DHT), potently activating AR and driving tumor progression. Advanced prostate cancer is initially treated with gonadal testosterone depletion, which suppresses this cascade of events and typically leads to a treatment response. Eventually, resistance to testosterone deprivation occurs with "castration-resistant" prostate cancer (CRPC) and is driven by the intratumoral synthesis of DHT. The generation of DHT occurs in large part from adrenal 19-carbon precursor steroids, which are dependent on expression of CYP17A1. Although the path from adrenal precursor steroids to DHT was generally thought to require 5α-reduction of testosterone, recent data suggest that it instead involves conversion from Δ-androstenedione by steroid-5α-reductase isoenzyme-1 to 5α-androstanedione, followed by subsequent conversion to DHT. The 5α-androstanedione pathway to DHT therefore bypasses testosterone entirely. Abiraterone acetate effectively inhibits CYP17A1, blocks the synthesis of androgens, and extends the survival of men with CRPC. Further progress in the hormonal treatment of CRPC is dependent on an understanding of the mechanisms that underlie CRPC and resistance to abiraterone acetate.

Figure 1

The pathway overview of DHT synthesis. The synthesis of intratumoral DHT requires enzymatic modification of the 3-, 5-, and 17-positions of the steroid backbone by 3β-hydroxysteroid dehydrogenase (3βHSD), steroid 5α-reductase (SRD5A) and 17β-hydroxysteroid dehydrogenase (17βHSD) isoenzymes. The widely accepted conventional pathway requires conversion of AD to T (red arrows). An alternative possibility circumvents the requirement for T by 5α-reduction of AD to 5α-dione (green arrows).