title: Endocrine-immune-paracrine interactions in prostate cells as targeted by phytomedicines.
abstract: Dehydroepiandrosterone (DHEA) is used as a dietary supplement and can be metabolized to androgens and/or estrogens in the prostate. We investigated the hypothesis that DHEA metabolism may be increased in a reactive prostate stroma environment in the presence of proinflammatory cytokines such as transforming growth factor beta1 (TGFbeta1), and further, whether red clover extract, which contains a variety of compounds including isoflavones, can reverse this effect. LAPC-4 prostate cancer cells were grown in coculture with prostate stromal cells (6S) and treated with DHEA +/- TGFbeta1 or interleukin-6. Prostate-specific antigen (PSA) expression and testosterone secretion in LAPC-4/6S cocultures were compared with those in monocultured epithelial and stromal cells by real-time PCR and/or ELISA. Combined administration of TGFbeta1 + DHEA to cocultures increased PSA protein secretion two to four times, and PSA gene expression up to 50-fold. DHEA + TGFbeta1 also increased coculture production of testosterone over DHEA treatment alone. Red clover isoflavone treatment led to a dose-dependent decrease in PSA protein and gene expression and testosterone metabolism induced by TGFbeta1 + DHEA in prostate LAPC-4/6S cocultures. In this coculture model of endocrine-immune-paracrine interactions in the prostate, TGFbeta1 greatly increased stromal-mediated DHEA effects on testosterone production and epithelial cell PSA production, whereas red clover isoflavones reversed these effects.
authors.affiliation: Endocrine Section, Laboratory of Clinical Investigation, Division of Intramural Research, National Center for Complementary and Alternative Medicine, NIH, Bethesda, Maryland, USA.
authors.forename: Nora E
authors.initials: NE
authors.lastname: Gray
authors.forename: Xunxian
authors.initials: X
authors.lastname: Liu
authors.forename: Renee
authors.initials: R
authors.lastname: Choi
authors.forename: Marc R
authors.initials: MR
authors.lastname: Blackman
authors.forename: Julia T
authors.initials: JT
authors.lastname: Arnold
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D004703:Endocrine System / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D008297:Male; D019899:Paracrine Communication; D008517:Phytotherapy; D010936:Plant Extracts / Q000627:therapeutic use*; D011467:Prostate / Q000166:cytology; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D027842:Syzygium / Q000737:chemistry; D013739:Testosterone / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D000099222:betaIG-H3 Protein
chemical_list: D000276:Adjuvants, Immunologic; D003687:Dehydroepiandrosterone; D016326:Extracellular Matrix Proteins; D015850:Interleukin-6; D010936:Plant Extracts; D017430:Prostate-Specific Antigen; D013739:Testosterone; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein