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Pippione et al. Steroidogenic enzymes in prostate cancer

Table 2: Different expression level of CYP17A1, AKR1C3, HSD17B3 and SRD5A enzymes during progression of PCa
Enzyme Presence Ref.
CYP17A1 Expressed in all PCa and upregulated in CRPC [15]
AKR1C3 Expressed 10-16 fold higher in several PCa cell lines with respect to healthy prostate cells and up to 3 fold [9]
in androgen responsive and androgen independent PCa cell xenografts upon androgen deprivation
Upregulated in CRPC, both within the tumor microenvironment and in soft-tissue metastasis [15-17,52,176,177]
HSD17B3 Expressed almost exclusively in the testis, there are some reports of its over-expression in PCa tissues. [15,22]
HSD17B3 mRNA was increased over 30 fold in PCa biopsies and the enzyme has been shown to be
upregulated 8-fold in LuCaP-23 and LuCAP-35 PCa cell lines, obtained from metastatic tissues of a
patient resistant to castration therapy
SRD5 A1 During PCa development its expression increases. A 2-4 fold increase of SRD5A1 expression, induced by [88,89,178-181]
activation of AR, has been observed in three androgen-responsive PCa cell lines
A2 Predominant isoform expressed in the normal prostate. During PCa development, its expression
decreases. AR represses SRD5A2 expression
A3 Overexpressed in hormone-refractory PCa tissues [182]
PCa: prostate cancer; AR: androgen receptor; CRPC: castration-resistant prostate cancer

pathway is formed by CYP17A1 via metabolism of 17α-hydroxypregnenolone to the second position,
pregnan-3α-hydroxy-20-one. The need for this enzyme thus increasing the rate of the lyase reaction. These
in all the metabolic pathways that allow and maintain structural studies provide a rationale to increase our
the activation of the AR in the prostatic cells makes understanding of this enzyme’s dual hydroxylase and
CYP17A1 one of the most important therapeutic lyase activity and facilitate the design of inhibitors that
targets in the biosynthesis pathway. may specifically interact with the androgen-generating
lyase activity, ultimately leading to novel therapeutics
To date, there are eight co-crystal structures of with improved efficacy.
CYP17A1 complexed with an inhibitor or substrate
and revealing the characteristic cytochrome P450 Several well-characterised CYP17A1 inhibitors have
fold [31] . The crystal structure of CYP17A1 bound either been discovered over the years for the treatment of
to abiraterone [Figure 3A] or to galeterone (TOK-001), advanced PCa [Figures 4 and 5] and several excellent
[35]
two clinically trailed CYP17A1 inhibitors (2 and 3, reviews have been published on this topic . Only
Figure 4), show that both inhibitors bind the haem iron abiraterone (2, Figure 4) has been approved for
at a 60° angle above the haeme plane while aligning clinical use for the treatment of CRPC. Abiraterone,
their chemical structures against the central helix with administered as an acetate prodrug, consists of a
the 3β-OH interacting with Asn 202 in the F helix [32] . steroidal scaffold with a pyridin-3-yl moiety in position
17 that inhibits CYP17A1 through coordination to the
haem iron [32] . This coordination obstructs the binding
More recently the co-crystal structure of CYP17A1 of endogenous substrates, leading to the competitive
mutant Ala105Leu in complex with hydroxylase inhibition of CYP17A1. Recently, the steroidal
substrates pregnenolone [Figure 3B], progesterone, CYP17A1 inhibitor galeterone (3, TOK-001) [36] , has
17,20-lyase substrates 17α-hydroxyprogesterone and been shown to be three times more potent than
17α-hydroxypregnenolone, showed that the general abiraterone in CYP17 enzyme activity assays [37] .
orientation of all physiological substrates in the active
site is quite similar to the one observed for abiraterone. Together, the steroidal scaffold and the aromatic
Each substrate is aligned in a position that allows the nitrogen-containing ring give to abiraterone a
formation of a hydrogen bond with the Asn202 side promiscuous profile with affinity toward steroid
chain. The 17α-hydroxypregnenolone, a substrate of receptors and other CYP enzymes, which are likely
lyase activity, could also assume a second pose, that is to contribute to the undesirable side effects observed
closer to the catalytic iron and further away for Asn202, in patients receiving abiraterone treatment including
hence preventing the formation of a hydrogen bond liver dysfunction, characterised by elevated total
as observed in the first position [33] . This observation bilirubin, aspartate aminotransferase and alanine
could explain the substrate selectivity of the lyase aminotransferase [38] .
reaction and the increased 17,20-lyase activity after
the allosteric binding of cytochrome b5. NMR studies Thus, these potential adverse effects of steroidal drugs
have already established that b5 binds differently triggered the efforts to develop nonsteroidal CYP17A1
to CYP17A1 depending on whether the substrate inhibitors. Combinatorial synthesis programmes
is pregnenolone or 17α-hydroxypregnenolone [34] . have been initiated by pharmaceutical companies
Cytochrome b5 could alter the positioning of to identify non-steroidal inhibitors to avoid the side

Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ December 12, 2017 333