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Endocrine-Immune-Paracrine Interactions in Prostate Cells as Targeted by Phytomedicines

Authors' Affiliation: Endocrine Section, Laboratory of Clinical Investigation, Division of Intramural Research, National Center for Complementary and Alternative Medicine, NIH, Bethesda, Maryland

Requests for reprints: Julia T. Arnold, Endocrine Section, Laboratory of Clinical Investigation, National Center for Complementary and Alternative Medicine, Building 10, Room 2B47, 9000 Rockville Pike, Bethesda, MD 20892-1547. Phone: 301-451-6711; Fax: 301-480-4570; E-mail: jarnold{at}mail.nih.gov.

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 β1 (TGFβ1), 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 +/– TGFβ1 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 TGFβ1 + DHEA to cocultures increased PSA protein secretion two to four times, and PSA gene expression up to 50-fold. DHEA + TGFβ1 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 TGFβ1 + DHEA in prostate LAPC-4/6S cocultures. In this coculture model of endocrine-immune-paracrine interactions in the prostate, TGFβ1 greatly increased stromal-mediated DHEA effects on testosterone production and epithelial cell PSA production, whereas red clover isoflavones reversed these effects.

Key Words: DHEA • TGFβ1 • stromal • prostate • PSA • testosterone • coculture • red clover isoflavones