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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.

carcinogenesis

Transforming growth factor β1 increase of hydroxysteroid dehydrogenase proteins is partly suppressed by red clover isoflavones in human primary prostate cancer-derived stromal cells