11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer

Monique Barnard, Jonathan L. Quanson, Elahe Mostaghel, Elzette Pretorius, Jacky L. Snoep, Karl Heinz Storbeck*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

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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 languageEnglish
Pages (from-to)192-201
Number of pages10
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume183
Early online date21 Jun 2018
DOIs
Publication statusPublished - 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

FundersFunder number
Medical Research Council of South Africa
NRF/DSTNRF-SARCHI-82813
National Research Foundation of South Africa98886
National Institutes of HealthP01 CA163227
U.S. Department of DefenseW81XWH-12-1-0208, W81XWH-15-1-0150
National Cancer InstituteP50CA097186

    Keywords

    • 11-Ketotestosterone
    • 11-Oxygenated androgens
    • 17β-Hydroxysteroid dehydrogenase type 2
    • Aldo-keto reductase 1C3
    • Castration resistant prostate cancer

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