Our current investigations center on the effects of selected androgenic (DHEA), estrogenic (phytoestrogens) or other dietary supplements and/or botanical agents on neoplastic prostate stromal and epithelial cell growth, genbe expression, and biochemical function, including cell-cell signaling. As a precursor to both estrogen and testosterone, DHEA may pose a potential cancer risk in hormone responsive tissues such as the prostate. We have sought to determine whether in vitro administration of DHEA exerts androgenic effects on prostate stromal and cancer cells by comparing protein expression and proliferation in cells treated with DHEA versus T and dihydrotestosterone (DHT). Included in the targets of hormone-induced proteins were members of the insulin-like growth factor (IGF) axis, which are involved in prostate stromal-epithelial signaling. High levels of IGF-1 and IGF binding protein -2 (IGFBP-2) have been associated with prostate cancer. Also prostate specific antigen (PSA) acts as an IGFBP-3 protease. Androgen receptor positive (AR+) LNCaP epithelial cells and primary prostate stromal cells were treated with DHEA, DHT or T at varying doses and for differing times. Cell proliferation assays showed a 2 to 4-fold increase in LNCaP cell numbers with DHT and T and delayed or no increase with DHEA treatment. Stromal cell proliferation did not change in any treatment group. The DHEA-induced protein and mRNA expression patterns of AR, PSA and IGF type I receptor (IGF-IR) were similar to those stimulated by T and DHT. LNCaP AR mRNA levels appeared to decrease with both DHEA and DHT treatments while the protein levels were stabilized and unchanged.. LNCaP production of PSA increased 4-5 fold in DHEA treated cells, versus up to 7-fold in the DHT treated cells. Hormone-induced IGF-IR expression peaked within 2 days in the LNCaP cells, with all hormones augmenting expression 2-3-fold. In stromal cells, DHEA-induced AR expression was decreased in magnitude and occurred more slowly than that induced by DHT or T. Stromal IGF-IR showed no hormone-induced variation in expression. Levels of IGF-II and IGFBP-2 did not appear to change with hormonal treatments. These data suggest that DHEA administration to LNCaP prostate cancer cells can modulate PSA, AR and IGF-IR protein expression similar to that of T and DHT, but exerts delayed and reduced effects on cell proliferation. To assess the extent to which these findings in LNCaP cells may be related to the mutant AR present in these cells, we are also comparing the effects of DHEA vs DHT and T in prostate cancer cells at different stages of neoplasitic development, and with varying AR status.
