AKR1C3 (type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase): Roles in malignancy and endocrine disorders

Molecular and Cellular Endocrinology
Trevor M Penning

Abstract

Aldo-Keto-Reductase 1C3 (type 5 17β-hydroxysteroid dehydrogenase (HSD)/prostaglandin (PG) F2α synthase) is the only 17β-HSD that is not a short-chain dehydrogenase/reductase. By acting as a 17-ketosteroid reductase, AKR1C3 produces potent androgens in peripheral tissues which activate the androgen receptor (AR) or act as substrates for aromatase. AKR1C3 is implicated in the production of androgens in castration-resistant prostate cancer (CRPC) and polycystic ovarian syndrome; and is implicated in the production of aromatase substrates in breast cancer. By acting as an 11-ketoprostaglandin reductase, AKR1C3 generates 11β-PGF2α to activate the FP receptor and deprives peroxisome proliferator activator receptorγ of its putative PGJ2 ligands. These growth stimulatory signals implicate AKR1C3 in non-hormonal dependent malignancies e.g. acute myeloid leukemia (AML). AKR1C3 moonlights by acting as a co-activator of the AR and stabilizes ubiquitin ligases. AKR1C3 inhibitors have been used clinically for CRPC and AML and can be used to probe its pluripotency.

Citations

May 11, 2019·Expert Opinion on Investigational Drugs·Fabio BarraSimone Ferrero
May 5, 2021·Chinese Medical Journal·Xin-Zhu XiaoFeng-Lin Chen
Mar 18, 2021·Environmental Toxicology and Chemistry·Nadia Coronado-PosadaJesus Olivero-Verbel
Jul 3, 2021·Cells·Álvaro Jara-Gutiérrez, Victoriano Baladrón
Jul 28, 2021·Pharmacological Reviews·Trevor M PenningTea Lanišnik Rižner
May 29, 2020·Journal of Medicinal Chemistry·Yang LiuHaopeng Sun
Dec 6, 2021·Endocrinology·Fitya MozarMonica M Montano
Jan 25, 2022·Experimental and Therapeutic Medicine·Zhaohui HuZhiwen Ding

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