Transforming growth factor ?1 increase of hydroxysteroid dehydrogenase proteins is partly suppressed by red clover isoflavones in human primary prostate cancer-derived stromal cells.

ABSTRACT: Transforming growth factor ?1 (TGF-?1) 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)-?-induced androgenicity. Mechanisms controlling those activities were explored. Three hydroxysteroid dehydrogenases (HSDs), 3?-HSD, HSD-17?1 and HSD-17?5 involved in metabolizing DHEA to testosterone (TESTO) were investigated. Individual depletion of HSDs in 6S cells significantly reduced TGF-?1/DHEA-induced PSA in LAPC-4 cells in cocultures. Monomer amounts of 3?-HSD were similar without or with TGF-?1 in both cell types but aggregates of 3?-HSD in 6S cells were much higher than those in LAPC-4 cells and were upregulated by TGF? in 6S cells. Basal and TGF-?1-treated levels of HSD-17?1 and HSD-17?5 in LAPC-4 cells were significantly lower than in 6S cells, whereas levels of HSD-17?1 but not HSD-17?5 were TGF? inducible. 6S cell HSD genes expression induced by TGF? or androgen signaling was insignificant to contribute TGF-?1/DHEA-upregulated protein levels of HSDs. RC decreased TGF-?1- upregulation of aggregates of 3?-HSD but not HSD-17?1. Depletion of TGF? receptors (TGF? Rs) reduced TGF-?1/DHEA-upregulated HSDs and TESTO. Immunoprecipitation studies demonstrated that TGF-?1 disrupted associations of TGF? Rs/HSDs aggregates, whereas RC suppressed the dissociations of aggregates of 3?-HSD but not HSD-17?1 from the receptors. Given that TGF? Rs are recycled with or without ligand, TGF-?1-induced disassociation of the HSDs from TGF? Rs may increase stability and activity of the HSDs. These data suggest a pathway connecting overproduction of TGF? with increased PSA in prostate cancer.

SUBMITTER: Liu X 

PROVIDER: S-EPMC3218644 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature