title: Aldo-keto reductase family 1 member C3 (AKR1C3) is a biomarker and therapeutic target for castration-resistant prostate cancer.
abstract: Current endocrine treatment for advanced prostate cancer does not result in a complete ablation of adrenal androgens. Adrenal androgens can be metabolized by prostate cancer cells, which is one of the mechanisms associated with progression to castration-resistant prostate cancer (CRPC). Aldo-keto reductase family 1 member C3 (AKR1C3) is a steroidogenic enzyme that plays a crucial role in the conversion of adrenal androgen dehydroepiandrosterone (DHEA) into high-affinity ligands for the androgen receptor (testosterone [T] and dihydrotestosterone [DHT]). The aim of this study was to examine whether AKR1C3 could be used as a marker and therapeutic target for CRPC. AKR1C3 mRNA and protein levels were upregulated in CRPC tissue, compared with benign prostate and primary prostate cancer tissue. High AKR1C3 levels were found only in a subset of CRPC patients. AKR1C3 can be used as a biomarker for active intratumoral steroidogenesis and can be measured in biopsy or transurethral resection of the prostate specimens. DuCaP (a CRPC cell line that has high AKR1C3 expression levels) used and converted DHEA under hormone-depleted conditions into T and DHT. The DHEA-induced growth of DuCaP could be antagonized by indomethacine, an inhibitor of AKR1C3. This study indicates that AKR1C3 can be considered a therapeutic target in a subgroup of patients with high AKR1C3 expression.
authors.affiliation: Department of Urology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Agus Rizal A H
authors.initials: AR
authors.lastname: Hamid
authors.forename: Minja J
authors.initials: MJ
authors.lastname: Pfeiffer
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Verhaegh
authors.forename: Ewout
authors.initials: E
authors.lastname: Schaafsma
authors.forename: Andre
authors.initials: A
authors.lastname: Brandt
authors.forename: Fred C G J
authors.initials: FC
authors.lastname: Sweep
authors.forename: John P M
authors.initials: JP
authors.lastname: Sedelaar
authors.forename: Jack A
authors.initials: JA
authors.lastname: Schalken
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D000074425:Aldo-Keto Reductase Family 1 Member C3; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000378:metabolism; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000378:metabolism*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D058990:Molecular Targeted Therapy; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000601:surgery*; D013739:Testosterone / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D013196:Dihydrotestosterone; D013739:Testosterone; D003687:Dehydroepiandrosterone; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; D007213:Indomethacin