title: Activin A stimulates AKR1C3 expression and growth in human prostate cancer.
abstract: Local androgen synthesis in prostate cancer (PC) may contribute to the development of castration-resistant PC (CRPC), but pathways controlling intratumoral steroidogenic enzyme expression in PC are unknown. We investigated the effects of activin, a factor involved in the regulation of PC growth and steroidogenic enzyme expression in other steroidogenic tissues, on intratumoral steroidogenesis in PC. Activin A effects and regulation of the activin-signaling pathway molecules were studied in the PC cell lines LNCaP, VCaP, and PC-3 and in 13 individual PC xenograft models. Also, expression levels of inhibin βA- and βB-subunits (INHBA and INHBB) and of the activin antagonist follistatin were quantitated in patient PC tissues. Activin A induced the expression and enzyme activity of 17β-hydroxysteroid dehydrogenase enzyme AKR1C3 in LNCaP and VCaP cells. Inhibition of endogenous activin A action in the PC-3 cell line decreased AKR1C3 levels and consequently testosterone synthesis. In return, androgens suppressed INHBA expression in both VCaP cells and the PC xenograft models. The antiproliferative effects of activin A were opposed by physiological concentrations of androstenedione in LNCaP cells. In patient PC tissues, expression levels of INHBA were increased in CRPC samples and correlated with AKR1C3 levels. Moreover, a high ratio of activin subunits to follistatin was associated with a worse metastasis-free survival in patients. In conclusion, activin A is controlled by androgens in PC models and regulates local androgen production. Activin A thus seems to mediate (residual) intratumoral androgen levels and could form a novel therapeutic target in CRPC.
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands. j.hofland@erasmusmc.nl
authors.forename: Johannes
authors.initials: J
authors.lastname: Hofland
authors.forename: Wytske M
authors.initials: WM
authors.lastname: van Weerden
authors.forename: Jacobie
authors.initials: J
authors.lastname: Steenbergen
authors.forename: Natasja F J
authors.initials: NF
authors.lastname: Dits
authors.forename: Guido
authors.initials: G
authors.lastname: Jenster
authors.forename: Frank H
authors.initials: FH
authors.lastname: de Jong
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000096:biosynthesis*; D028341:Activins / Q000378:metabolism*; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000728:Androgens / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000378:metabolism*; D015398:Signal Transduction; D013739:Testosterone / Q000378:metabolism
chemical_list: D000728:Androgens; C422405:activin A; D028341:Activins; D013739:Testosterone; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3