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Pippione et al. Steroidogenic enzymes in prostate cancer

Figure 2: The principal and the two alternative androgen biosynthetic pathways: the canonical pathway is shown on white background,
the backdoor pathway is shown on yellow background and the 5a-dione pathway on light blue background. In the squares, production of T
and DHT in the development of PCa are shown. PCa: prostate cancer; T: testosterone; DHT: dihydrotestosterone; CYP17A1: cytochrome
P450 17A1; HSD3B: 3b-hydroxysteroid dehydrogenase; HSD17B2/3/10: 17b-hydroxysteroid dehydrogenase type 2/3/10; SRD5A: steroid
5a-reductases; AKR1C1/2/3: aldo-keto reductase family 1, member 1/2/3; RDH5: retinol dehydrogenase type 5; AD: androstenedione

and the AR by a bifunctional targeting molecule. In epigenetic control is however suggested by studies
the following chapters, we will focus on CYP17A1, on the inductive effect of 5aza-dC on TFs required
AKR1C3, HSD17B3 and SRD5A, as these enzymes for CYP17A1 expression [28] . This membrane-bound
play essential roles in all the three pathways protein has both 17α-hydroxylase and a 17,20-lyase
mentioned above. In Table 2, their different expression activity. The 17α-hydroxylase activity is important
level during the progression of PCa is described. for the production of the glucocorticoid cortisol,
Finally, we will review the AR as an additional target whereas the 17,20-lyase activity leads to androgen
[29]
for the design of bifunctional drugs. production . The lyase activity is stimulated in a
concerted fashion by cytochrome b5 and appears to
be an allosteric function rather than via conventional
CYP17A1 electron transfer mechanism of this co-enzyme [30] .
Cytochrome P450 17A1 (CYP17A1, P450c17) plays a CYP17A1 is required in the three parallel pathways to
major role in the steroidogenic pathway that produces catalyse the hydroxylation of the steroid ring carbon 17
androgens and estrogens. It is expressed principally of pregnenolone to form 17α-hydroxypregnenolone and
in the adrenal gland and gonads. In humans, the progesterone to form 17α-hydroxyprogesterone (major
expression of CYP17A1 is driven by a complex product, Figure 2) and 16α-hydroxyprogesterone
interaction of different transcription factors (TFs) and, (minor product).The resulting metabolites undergo the
differently from rodents [25] , it appears not directly 17,20-lyase reaction by the same enzyme involving
influenced by epigenetic regulation [26,27] . Indeed, the cleavage of the side-chain of the steroid nucleus
CpG islands, the sites of the epigenetic methylation, in order to obtain DHEA and AD, respectively. The
are absent in human CYP17A1 gene [25] . Indirect androsterone, precursor of DHT in the backdoor

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