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

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 sig- nificantly 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.

SEEK ID: https://fairdomhub.org/publications/457

DOI: 10.1016/j.jsbmb.2018.06.013

Projects: Steroid biosynthesis

Publication type: Not specified

Journal: The Journal of Steroid Biochemistry and Molecular Biology

Citation: The Journal of Steroid Biochemistry and Molecular Biology 183 : 192

Date Published: 1st Oct 2018

Registered Mode: Not specified

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

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Citation
Barnard, M., Quanson, J. L., Mostaghel, E., Pretorius, E., Snoep, J. L., & Storbeck, K.-H. (2018). 11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer. In The Journal of Steroid Biochemistry and Molecular Biology (Vol. 183, pp. 192–201). Elsevier BV. https://doi.org/10.1016/j.jsbmb.2018.06.013
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Created: 5th Mar 2020 at 11:48

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