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

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.