Abstract
The progression of castration resistant prostate cancer (CRPC) is driven by the intratumoral conversion of adrenal androgen precursors to potent androgens. The expression of aldo-keto reductase 1C3 (AKR1C3), which catalyses the reduction of weak androgens to more potent androgens, is significantly increased in CRPC tumours. The oxidation of androgens to their inactive form is catalysed by 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2), but little attention is given to the expression levels of this enzyme. In this study, we show that the 11-oxygenated androgen precursors of adrenal origin are the preferred substrate for AKR1C3. In particular we show that the enzymatic efficiency of AKR1C3 is 8- and 24-fold greater for 11-ketoandrostenedione than for the classic substrates androstenedione and 5α-androstanedione, respectively. Using three independent experimental systems and a computational model we subsequently show that increased ratios of AKR1C3:17βHSD2 significantly favours the flux through the 11-oxygenated androgen pathway as compared to the classical or 5α-androstanedione pathways. Our findings reveal that the flux through the classical and 5α-androstanedione pathways are limited by the low catalytic efficiently of AKR1C3 towards classical androgens combined with the high catalytic efficiency of 17βHSD2, and that the expression of the oxidative enzyme therefore plays a vital role in determining the steady state concentration of active androgens. Using microarray data from prostate tissue we confirm that the AKR1C3:17βHSD2 ratio is significantly increased in patients undergoing androgen deprivation therapy as compared to benign tissue, and further increased in patients with CRPC. Taken together this study therefore demonstrates that the ratio of AKR1C3:17βHSD2 is more important than AKR1C3 expression alone in determining intratumoral androgen levels and that 11-oxygenated androgens may play a bigger role in CRPC than previously anticipated.
Original language | English |
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Pages (from-to) | 192-201 |
Number of pages | 10 |
Journal | Journal of Steroid Biochemistry and Molecular Biology |
Volume | 183 |
Early online date | 21 Jun 2018 |
DOIs | |
Publication status | Published - Oct 2018 |
Funding
This work is based on the research supported in part by the National Research Foundation of South Africa (Grant Number 98886 to KS), the NRF/DST in South Africa ( NRF-SARCHI-82813 to JLS), the Medical Research Council of South Africa (KS) the NIH Pacific Northwest Prostate Cancer SPORE ( P50 CA97186 to EAM), the NIH ( P01 CA163227 to EAM) and the DOD ( W81XWH-15-1-0150 and W81XWH-12-1-0208 to EAM). Appendix A
Funders | Funder number |
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Medical Research Council of South Africa | |
NRF/DST | NRF-SARCHI-82813 |
National Research Foundation of South Africa | 98886 |
National Institutes of Health | P01 CA163227 |
U.S. Department of Defense | W81XWH-12-1-0208, W81XWH-15-1-0150 |
National Cancer Institute | P50CA097186 |
Keywords
- 11-Ketotestosterone
- 11-Oxygenated androgens
- 17β-Hydroxysteroid dehydrogenase type 2
- Aldo-keto reductase 1C3
- Castration resistant prostate cancer