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Potential Prostate Cancer Drug Target: Bioactivation of Androstanediol by Conversion to Dihydrotestosterone

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Potential Prostate Cancer Drug Target: Bioactivation of Androstanediol by Conversion to Dihydrotestosterone Published OnlineFirst June 24, 2011; DOI: 10.1158/1078-0432.CCR-11-0644 Clinical Cancer Molecular Pathways Research Potential Prostate Cancer Drug Target: Bioactivation of Androstanediol by Conversion to Dihydrotestosterone James L. Mohler1,2,3, Mark A. Titus1, and Elizabeth M. Wilson2,3,4 Abstract High-affinity binding of dihydrotestosterone (DHT) to the androgen receptor (AR) initiates andro- gen-dependent gene activation, required for normal male sex development in utero, and contributes to prostate cancer development and progression in men. Under normal physiologic conditions, DHT is synthesized predominantly by 5a-reduction of testosterone, the major circulating androgen produced by the testis. During androgen deprivation therapy, intratumoral androgen production is sufficient for AR activation and prostate cancer growth, even though circulating testicular androgen levels are low. Recent studies indicate that the metabolism of 5a-androstane-3a,17b-diol by 17b-hydroxysteroid dehydrogenase 6 in benign prostate and prostate cancer cells is a major biosynthetic pathway for intratumoral synthesis of DHT, which binds AR and initiates transactivation to promote prostate cancer growth during androgen deprivation therapy. Drugs that target the so-called backdoor pathway of DHT synthesis provide an opportunity to enhance clinical response to luteinizing-hormone–releasing hormone (LHRH) agonists or antagonists, AR antagonists, and inhibitors of 5a-reductase enzymes (finasteride or dutasteride), and other steroid metabolism enzyme inhibitors (ketoconazole or the recently available abiraterone acetate). Clin Cancer Res; 17(18); 5844–9. Ó2011 AACR. Background stabilizes AR and increases transcriptional activity (2, 3). The well-established differences in potency between T and Normal male sex development and growth depend on DHT (4) result not from differences in AR equilibrium high-affinity binding of dihydrotestosterone (DHT; 5a- androgen-binding affinity but from the greater hydropho- androstan-17b-ol-3-one), the 5a-reduced product of tes- bicity of DHT that strengthens human AR intermolecular tosterone (T; 4-androsten-17b-ol-3-one), to the androgen interactions, slows the dissociation rate of bound andro- receptor (AR), an essential ligand-dependent transcription gen, and stabilizes the ligand-bound AR to render DHT a factor that regulates androgen-dependent gene transcrip- more active androgen than T (1, 5). tion. AR binds T and DHT with similar high-equilibrium The requirement for DHT in normal prostate growth and binding affinity (equilibrium dissociation constant, development of the external genitalia is shown by the 5a- Kd 0.3 nmol/L; ref. 1), and T and DHT are the only reductase syndrome. An inactivating mutation in the type 2 naturally occurring steroids that activate wild-type AR. AR is isoform of the 5a-reductase enzyme that converts T to DHT not activated directly by binding either 5a-androstane-3a, results in a small prostate gland and predominantly female 17b-diol (androstanediol) or dehydroepiandrosterone or ambiguous external phenotype in affected newborn (DHEA). Androgen specificity for AR transcriptional sig- males with 46 XY chromosomes (6). The 5a-reductase naling is achieved through the highly structured AR ligand- syndrome provides physiologic evidence that circulating binding domain and the selective ability of T and DHT to DHT arises from T and that DHT is required for normal a induce the AR NH2- and carboxyl-terminal interaction that male sex development. On the other hand, untreated 5 - reductase syndromepatients beginto virilizeat puberty. This observation suggests that the pubertal increase in Authors' Affiliations: 1Department of Urology, Roswell Park Cancer T compensates for low DHT, or that a pubertal increase in Institute, 2Department of Urology, University at Buffalo, State University a of New York, Buffalo, New York; 3Lineberger Comprehensive Cancer the type 1 isoform of 5 -reductase (7, 8)acts on other steroid Center, 4Laboratories for Reproductive Biology, Department of Pediatrics precursors, such as 17a-hydroxyprogesterone to form 5a- and Department of Biochemistry and Biophysics, University of North pregnane-17a-ol-3, 20-dione and eventually DHT (Fig. 1). Carolina, Chapel Hill, North Carolina AR is a critical transcriptional regulator required to estab- Corresponding Author: Elizabeth M. Wilson, Laboratories for Repro- lish the normal male sex phenotype and for the develop- ductive Biology, 3340 Medical Biomolecular Res. Bldg., Chapel Hill, NC 27599-7500. Phone: 919-966-5168; Fax: 919-966-2203; E-mail: ment and progression of prostate cancer (9–11). Regression [email protected] of prostate cancer after medical or surgical androgen depri- doi: 10.1158/1078-0432.CCR-11-0644 vation therapy is followed invariably by the development Ó2011 American Association for Cancer Research. of castration-recurrent or castration-resistant prostate 5844 Clin Cancer Res; 17(18) September 15, 2011 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst June 24, 2011; DOI: 10.1158/1078-0432.CCR-11-0644 Intratumoral 17b-HSD6 Conversion of Androstanediol to DHT HO Cholesterol P450scc O O O P450ox/red OH P450ox/red + P450c17 P450c17 Cyt b5 HO HO HO Pregnenolone 17α-OH-pregnenolone Dehydroepiandrosterone Abiraterone Abiraterone (DHEA) 17βHSD1 acetate acetate 3βHSD 3βHSD 3βHSD AKR1C3 O O O 17βHSD2 OH P450c17 OH P450c17 P450ox/red P450ox/red O O O HO Progesterone 17α-OH-progesterone Androstenedione Androstenediol (Androsta-5-ene-3β,17β-diol) 5αR1 5αR1 Dutasteride 17βHSD2 α 5αR3 β β 5 R3 O O 17 HSD3 3 HSD AKR1C3 OH P450ox/red OH P450c17 O O O Dihydroprogesterone 17α-OH-dihydroprogesterone Testosterone (5α-pregnane-3,20-dione) (5α-pregnane-17α-ol-3,20-dione) Abiraterone AKR1Cs AKR1Cs acetate 5αR1 3αHSD O 3αHSD O Dutasteride 5αR3 AR P450c17 OH 5αR2 P450c17 HO HO Finasteride O Allopregnanolone 17α-OH-allopregnanolone (5α-pregnane-3α-ol-20-one) (5α-pregnane-3α,17α-diol-20-one) (Tetrahydroprogesterone) 17βHSD3 Abiraterone 17βHSD6 O P450c17 acetate Androstanedione O α OH (5 -androstane-3,20-dione) 17βHSD2 17βHSD2 17βHSD6 OH HO O Androsterone 17βHSD3 5α-Dihydrotestosterone AKR1Cs (DHT) HO 3αHSD Androstanediol (5α-androstane-3α,17β-diol) (3α-androstanediol) © 2011 American Association for Cancer Research Figure 1. The backdoor pathway of DHT synthesis involves the conversion of androstanediol to DHT by 17b-HSD6. Conversion of cholesterol to prenenolone by the P450 side-chain cleavage enzyme (P450ssc) is the first committed step in steroid biosynthesis. The 17a-hydroxylase/17,20-lyase (P450c17) catalyzes multiple 17a-hydroxylase and 17,20-lyase reactions in the steroidogenic pathway that require P450 oxidoreductase (P450ox/red) electron transfer. P450c17 coded by the CYP17A1 gene is the target for inhibition by abiraterone acetate. Progesterone, 17a-hydroxyprogesterone (17a-OH-progesterone), and T are substrates for 5a-reductase type 1, 2, or 3 (5aR1, 2, or 3). Finasteride is a 5aR2 inhibitor. Dutasteride is an inhibitor of 5aR1, 5aR2, and 5aR3. Isozymes of 3b-hydroxysteroid dehydrogenase (3bHSD), 17b-hydroxysteroid dehydrogenase (17bHSD), and aldo-keto reductase (AKR1C3) are often reversible enzymes with oxidative and reductive activities that require nicotinamide adenine dinucleotide cofactors. T and DHT are the 2 biologically active androgens that activate AR. T is the major circulating active androgen formed in the testis. DHT is formed from T in the testis and can be synthesized in a so-called backdoor pathway (green) from progesterone and androsterone precursors, independent of DHEA, androstenedione, or T intermediates. www.aacrjournals.org Clin Cancer Res; 17(18) September 15, 2011 5845 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst June 24, 2011; DOI: 10.1158/1078-0432.CCR-11-0644 Mohler et al. cancer (CRPC), which shows an initial reliance of prostate androstanediol to DHT include 17b-hydroxysteroid dehy- cancer growth on AR-mediated gene transcription in drogenase 6 [17b-HSD6 or HSD17B6, also known as response to DHT. AR levels are often increased in CRPC, retinol dehydrogenase (RODH) 3a-HSD; ref. 39], 17b- consistent with the continued expression of AR-stimulated hydroxysteroid dehydrogenase 10 (17b-HSD10 or genes (12). Additional growth-stimulating mechanisms in HSD17B10; ref. 40), retinol dehydrogenase 5 (RDH5; CRPC include increased levels of AR coregulators, transcrip- ref. 39), dehydrogenase/reductase short-chain dehydrogen- tion factors, and/or phosphorylation, which render AR ase/reductase family member 9 (DHRS9; ref. 33, 41), and more sensitive to much lower levels of intratumoral andro- retinol dehydrogenase 4 (RODH4; ref. 42). gen and to growth factor and cytokine activation indepen- Recent studies suggest that benign human prostate and dent of androgen. AR mutations, although rare in prostate prostate cancer cells express predominantly 17b-HSD6 as cancer, can decrease specificity of AR steroid binding, which the major enzyme that converts androstanediol to DHT, results in a more promiscuous transcriptional activator that and it is DHT that accounts for AR transactivation in the responds to a broader range of ligands (13–16). presence of androstanediol (43). Precise measurements of Recent studies highlight the potential importance of relative enzyme activity of several hydroxysteroid dehydro- intratumoral androgen biosynthesis in
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