Comparative Effects of DHEA Versus Testosterone, Dihydrotestosterone and Estradiol on Proliferation and Gene Expression in Human LNCaP Prostate Cancer Cells

Serum levels of the adrenal androgen dehydroepiandrosterone (DHEA) peak in men and women in the 3rd decade of life and decrease progressively with age. Increasing numbers of middle-aged and older individuals consume over-the-counter preparations of DHEA hoping it will retard aging by increasing muscle and bone mass and strength, decreasing fat, and improving immunologic and neurobehavioral functions. Because DHEA can serve as a precursor to more potent androgens and estrogens, like testosterone (T), dihydrotestosterone (DHT), and estradiol (E2), supplemental DHEA use may pose a cancer risk in patients with nascent or occult prostate cancer. The steroid responsive human LNCaP prostate cancer cells, containing a functional, but mutated androgen receptor (AR) were used to compare effects of DHEA with those of T, DHT, and E2 on cell proliferation, and protein and/or gene expression of AR, PSA, IGF-I, IGF-I receptor (IGF-IR), IGF-II, IGF binding proteins –2,3, and 5, (IGFBPs-2-5), and estrogen receptor-β (ERβ). Cell proliferation assays revealed significant stimulation by all four steroids. DHEA and E2induced responses were similar, but delayed and reduced, compared with those of T and DHT. All four hormones increased gene and/or protein expression of PSA, IGF-IR, IGF-I, and IGFBP-2, and decreased those of AR, ERβ, IGF-II, and IGFBP-3. There were no significant effects of hormone treatment on IGFBP-5 mRNA. DHEA and E2 responses were similar, and distinct from those of DHT and T, in time and dose dependent studies. Further studies of the mechanisms of DHEA effects on prostate cancer epithelial cells of varying AR status, as well as on prostate stromal cells, will be required to discern the implications of DHEA supplementation on prostatic health.