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Pippione et al. Steroidogenic enzymes in prostate cancer

The canonical pathway pathway was contributing to the synthesis of androgens
This biosynthetic pathway is similar to that occurring in without the need for androgenic precursors. Here, the
the testes. Androgens are known to be synthesised de progesterone produced by the same reactions as in
novo starting from a number of precursor molecules the canonical pathway, is converted to androsterone
absorbed from the circulation, including cholesterol, by CYP17A1, SRD5A, and AKR1C2. These enzymes
progesterone and adrenal DHEA. Starting from are responsible for converting AD to Tin a similar
cholesterol, the first step is the conversion to C21 manner to HSD17B3 and AKR1C3 in the canonical
pregnenolone by the cholesterol aliphatic side-chain pathway, resulting in the conversion of androsterone
specific metabolic activity of mitochondrial CYP11A1. to 5α-androstane-3α,17β-diol. The final step of
The next steps lead to the synthesis of AD by two the pathway leading to DHT is catalysed by retinol
different pathway branches where the intermediates dehydrogenase type 5 (RDH5) [21,22] . This enzyme,
progesterone or DHEA are formed by CYP17A1 upregulated in mice with castration resistance [17,22] ,
or HSD3B respectively. The subsequent reduction mediates a key step in DHT biosynthesis and is one
of AD to T is catalysed by AKR1C3. T is further of the few steroidogenic enzymes acting at a single
reduced to DHT by SRD5A enzymes. In patients point in the biosynthetic pathway. Studies in LNCaP
with CRPC, DHEA, derived from the adrenal gland, xenografts indicate that the backdoor pathway might
is the predominant T precursor implicated in this be dominant when tumours are treated with inhibitors
pathway. The strongest evidence for the action of the of androgen synthesis, including ketoconazole and
canonical pathway in the prostate comes from a study finasteride, which inhibit CYP17A1, and SRD5A2,
[23]
published by Fankhauser et al. [14] which is focussed respectively .
on the incubation of cultures of prostate samples from
patients with benign prostatic hyperplasia (BPH), All these pathways (“canonical”, “backdoor” and
androgen-naive and/or hormone-refractory PCa with “5α-dione” pathways, Figure 2), ultimately aim at
various precursor substrates including cholesterol, generating the potent signalling androgen DHT.
Involving mainly the same enzymes, they differ
progesterone, AD, DHEA, and T. The results show the in terms of substrate preference and/or reaction
prominence of the conversion of AD to T, suggesting sequence. Their occurrence and relative importance
that the canonical pathway is the most pertinent T/ in the development and progression of PCa remains
DHT synthesis pathway in patients with PCa. These controversial, since the experimental evidence comes
conclusions are supported by findings that expression mainly from preclinical cell culture models, where
of the HSD17B isoenzymes, and in particular AKR1C3, different results are obtained depending on the cell
key enzymes responsible for the conversion of AD lines studied or where more clinically-relevant biopsy
to T, are upregulated in tumour biopsy samples from samples have been used for analysis. The current
patients with CRPC [15-17] . understanding of androgen synthesis and the evidence
for its role in castration resistance, either supporting
The 5α-dione pathway or rebutting the relevance of each pathway to patients
The 5α-dione pathway allows PCa cells to generate with PCa were recently extensively reviewed by
the potent signalling androgen DHT without the Stuchbery et al. [24] .
need for T as a substrate. In this pathway, the
order of reactions is reversed compared to the Inhibiting these steroidogenic enzymes that play vital
canonical biosynthesis: AD is initially 5α-reduced to roles in the biosynthesis of T and DHT seems to be
5α-androstanedione by SRD5A1 and then further an attractive strategy for the development of therapies
reduced to DHT by HSD17B3 [18,19] . In contrast, in for the treatment of PCa. The existence of alternative
the canonical biosynthesis AD is the substrate of pathways in PCa leading to the synthesis of T and
HSD17B3 that is reduced to T which is then further DHT supports the idea for the development of multi-
reduced to DHT by SRD5A. The 5α-dione pathway targeting strategies, involving both dual and multiple
was first described in 2011, and as such, fewer studies inhibitors of androgen-metabolising enzymes that
supporting this model are currently available compared are able to affect androgen synthesis and signalling
with the other two models of androgen synthesis, at different points in the biosynthesis. Therapeutic
although indirect evidence is available and supports strategies aimed at more efficiently targeting the
the clinical relevance of this pathway too [15,17] . steroidogenic pathway could involve the concomitant
use of inhibitors targeting two different enzymes or a
The backdoor androgen synthesis pathway unique dual-targeting inhibitor able to modulate more
This biosynthetic pathway was originally identified in than one enzyme in the steroidogenesis pathway.
Tammar wallabies in 2003 [20] . It was the first report A potential variation of this strategy involves the
to demonstrate that in the prostate the “backdoor” modulation of an androgen-metabolising enzyme
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ December 12, 2017 331