title: Transforming growth factor β1 increase of hydroxysteroid dehydrogenase proteins is partly suppressed by red clover isoflavones in human primary prostate cancer-derived stromal cells.
abstract: Transforming growth factor β1 (TGF-β1) increases dehydro-epiandrosterone (DHEA) metabolism to androgens and prostate-specific antigen (PSA) in a prostate tissue model where stromal (6S) cells and epithelial (LAPC-4) cells are cocultured. Red clover (RC) isoflavones inhibits transforming growth factor (TGF)-β-induced androgenicity. Mechanisms controlling those activities were explored. Three hydroxysteroid dehydrogenases (HSDs), 3β-HSD, HSD-17β1 and HSD-17β5 involved in metabolizing DHEA to testosterone (TESTO) were investigated. Individual depletion of HSDs in 6S cells significantly reduced TGF-β1/DHEA-induced PSA in LAPC-4 cells in cocultures. Monomer amounts of 3β-HSD were similar without or with TGF-β1 in both cell types but aggregates of 3β-HSD in 6S cells were much higher than those in LAPC-4 cells and were upregulated by TGFβ in 6S cells. Basal and TGF-β1-treated levels of HSD-17β1 and HSD-17β5 in LAPC-4 cells were significantly lower than in 6S cells, whereas levels of HSD-17β1 but not HSD-17β5 were TGFβ inducible. 6S cell HSD genes expression induced by TGFβ or androgen signaling was insignificant to contribute TGF-β1/DHEA-upregulated protein levels of HSDs. RC decreased TGF-β1- upregulation of aggregates of 3β-HSD but not HSD-17β1. Depletion of TGFβ receptors (TGFβ Rs) reduced TGF-β1/DHEA-upregulated HSDs and TESTO. Immunoprecipitation studies demonstrated that TGF-β1 disrupted associations of TGFβ Rs/HSDs aggregates, whereas RC suppressed the dissociations of aggregates of 3β-HSD but not HSD-17β1 from the receptors. Given that TGFβ Rs are recycled with or without ligand, TGF-β1-induced disassociation of the HSDs from TGFβ Rs may increase stability and activity of the HSDs. These data suggest a pathway connecting overproduction of TGFβ with increased PSA in prostate cancer.
authors.affiliation: Endocrine Section, Intramural Research Program, National Center for Complementary and Alternative Medicine, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, MD 20892, USA. xunxianl@mail.nih.gov
authors.forename: Xunxian
authors.initials: X
authors.lastname: Liu
authors.forename: Yun-Shang
authors.initials: YS
authors.lastname: Piao
authors.forename: Julia T
authors.initials: JT
authors.lastname: Arnold
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000074425:Aldo-Keto Reductase Family 1 Member C3; D002478:Cells, Cultured; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D007529:Isoflavones / Q000494:pharmacology*; D008297:Male; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D029921:Trifolium / Q000737:chemistry*
chemical_list: D007529:Isoflavones; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D013739:Testosterone; D015096:3-Hydroxysteroid Dehydrogenases; D006913:Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human; D017430:Prostate-Specific Antigen