Poster Sessions

CANCER-27

Julia Arnold

J. Arnold, S. Sharma, H. Le, N. Gray, X. Liu

TGF-beta Effects on Hydroxysteroid Dehydrogenase Enzymes and Testosterone Production in Prostate Reactive Stromal Microenvironment

Dehydroepiandrosterone (DHEA) is commonly used in the USA as a dietary supplement and can be metabolized to androgens and/or estrogens in the prostate, which may affect prostate pathophysiology. Reactive prostate stroma is associated with the cancer tissue micro-environment, and may contribute to increased androgenic metabolism of DHEA. In previous studies, DHEA treatment of LAPC-4 prostate cancer cells grown in coculture with prostate stromal cells (“6S”), stimulated prostate specific androgen (PSA) production, whereas little PSA was produced in monocultured LAPC-4 cells. Addition of TGFb1/DHEA to the cocultures simulated a reactive stromal microenvironment and increased PSA protein secretion 2-4 times and gene expression up to 50-fold, over DHEA alone as well as increased metabolism of DHEA to testosterone. Three enzymes (3b-HSD, 17b-HSD1, and 17b-HSD5) were investigated that are involved in metabolizing DHEA to testosterone. Treatment of LAPC-4/6S cocultures with siRNAs to individual HSD enzymes depleted the enzymes in 6S cells but not LAPC-4 cells and reduced by >50% LAPC-4 PSA protein expression when treated with TGFb1/DHEA compared to the control. TGFb1 effects on HSD protein expression was measured in 6S cells and LAPC-4 cells. These data highlight the importance of HSD enzymes in 6S-stromal-mediated effects on LAPC-4 PSA production and suggest that TGFb1 exerts effects on expression and activity of steroid metabolizing enzymes and alters associations with TGF-b receptors.