Androgen metabolism in prostate cancer: from molecular mechanisms to clinical consequences

Abstract

Despite our most vigorous efforts, prostate cancer remains the second leading cause of cancer death in men. Understanding the intricacies of androgen metabolism is vital to finding therapeutic targets, particularly with progression of advanced prostate cancer after initial hormone therapy, where adrenal precursors are involved. Such is the case with castration-resistant prostate cancer, where adrenal androgens, for example, dehydroepiandrosterone, are a source for intratumoural synthesis of dihydrotestosterone. As prostate cancer progresses, androgen metabolism changes due to altered expression of steroidogenic enzymes and mutations in the components of the steroidogenic machinery. These alterations sustain disease and allow progression; mechanistically, they may also enable development of hormone therapy resistance. With the development of the newer agents, abiraterone acetate and enzalutamide, efforts have been made to better define the basis for response and resistance. This work can be carried out in cell lines, animal models, as well as with ex vivo analysis of tissues obtained from patients. Efforts to further elucidate the finer details of the steroidogenic pathway are necessary to move toward a curative paradigm for patients with localised disease at high risk for recurrence.

Figure 1

Conversion from DHEA to DHT requires 3β-hydroxysteroid dehydrogenase (3βHSD), steroid-5α-reductase (SRD5A), and 17β-hydroxysteroid dehydrogenase (17βHSD) isoenzymes. The initial rate-limiting reaction converts the 3β-hydroxyl group to a 3-keto moiety and isomerises the Δ⁵ to a Δ⁴ structure, which is catalysed by 3βHSD and produces AD as an intermediate metabolite. In the conversion of AD to DHT, metabolic flux can occur either through AD→T→DHT (the conventional pathway, shown in red) or AD→5α-dione→DHT (the 5α-dione pathway, shown in blue). The 5α-dione pathway is the major pathway utilised for DHT synthesis from adrenal precursors in CRPC. Abbreviations: 3αHSD, 3α-hydroxysteroid dehydrogenase; AD, Δ⁴-androstenedione; A5diol, Δ⁵-androstene-3β,17β-diol.