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Pippione et al. Steroidogenic enzymes in prostate cancer

Table 1: Therapies and approved drugs for PCa treatment according to its progression
PCa progression Therapy Mechanisms Drugs Structure or number in the text
Localised Surgery
disease Radiation
ADT GnRH agonists and antagonists Buserelin Synthetic peptide
Goserelin Synthetic peptide
Leuprolide Synthetic peptide
Triptorelin Synthetic peptide
Degarelix Synthetic peptide
Advanced PCa ADT AR antagonist Steroidal Cyproterone 50
Non steroidal Flutamide 51
Nilutamide 52
Bicalutamide 53
CRPC ADT AR antagonist Non steroidal Enzalutamide 54
Androgen synthesis inhibitors (CYP17 Abiraterone 2
inhibitors)
Chemoterapy Inductors of microtubule Docetaxel Taxane
stabilization Cabazitaxel Taxane
Metabolic radiation Alpharadin Radium-223
Vaccine Sipuleucel-T -
Monoclonal antibody Denosumab -
PCa: prostate cancer; ADT: androgen deprivation therapy; AR: androgen receptor; GnRH: gonadotropin-releasing hormone analogues;
CRPC: castration-resistant prostate cancer
deprivation therapy (ADT) via chronic administration AR machinery and support tumour cell growth and
of gonadotropin-releasing hormone analogues, anti- survival [11] . Additionally, a number of studies have
androgens or a combination of these drugs [Table 1]. indicated several enzymes are able to facilitate the
ADT is considered the standard choice of treatment for intratumoral neo-synthesis or conversion of circulating
[3]
men with de novo or recurrent metastatic disease . adrenal androgen precursors to the active AR
Initially, ADT provides palliation of symptoms, but ligands [12] .
the therapeutic effects of castration are usually
short lived, with 70% of patients developing signs This review is focussed on outlining and discussing the
of disease progression within 2 years despite very key players in the steroidogenic pathway that is tightly
low levels of circulating testosterone (T) [4,5] . Many linked with the AR activation.
patients will inevitably relapse and ultimately develop
castration-resistant prostate cancer (CRPC), which is THE STEROIDOGENIC CASCADE INVOLVED
responsible for the vast majority of PCa mortalities. IN PCA
Although the mechanisms of resistance are multi-
[6]
factorial, the androgen axis still plays a major role .
Evidence accumulated over the past decade clearly Under normal physiological conditions about 60%
indicates that castration-resistant growth, to a large of androgens produced in the prostate come from
extent, is driven by continued AR signalling, despite circulating T synthesised from cholesterol in the testis.
castration resulting in only low levels of T in the serum. The remainder derives from dehydroepiandrosterone
Emerging literature indicates a complex network of (DHEA) synthesised in the zona reticularis of
molecular players linked in part with amplification or the adrenal glands [Figure 1]. The prostate itself
mutations in androgen receptors allowing activation by contributes to androgen anabolism by reducing
progesterone, estrogens and androgen antagonists, testicular T to the more potent AR ligand DHT
generation of alternative splicing variants or with and converting DHEA to T and DHT [Figure 2].
androgen neo-synthesis within the prostate tumour The enzymes converting T to DHT are type 1 or
or adrenals [7-10] . Accordingly, both the management 2 5α-reductase (SRD5A), the type 2 being the
of PCa patients and complete abolition of androgens predominant isoform in prostate. This mechanism of
are difficult to achieve. Direct measurement of production of DHT presumably allows the prostate to
androgen levels in clinical samples from patients maintain constitutive levels of AR that are sufficient
with CRPC reveal residual T (0.2-2.94 ng/g) and for activity in the luminal epithelium. The adrenal
dihydrotestosterone (DHT, 0.36-2.19 ng/g) levels in DHEA taken up by prostate cells as the sulphate
tissue samples, respectively; nonetheless these levels derivative is reduced to androstenedione (AD) by a
are considered more than sufficient to activate the 3β-hydroxysteroid dehydrogenase type 1 (HSD3B1)

Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ December 12, 2017 329