Comparative effects of DHEA vs. testosterone, dihydrotestosterone, and estradiol on proliferation and gene expression in human LNCaP prostate cancer cells

1 Endocrine Section, Laboratory of Clinical Investigation, Division of Intramural Research, and 2 Office of Clinical and Regulatory Affairs, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland Submitted 24 September 2004 ; accepted in final form 1 November 2004 Serum levels of the adrenal androgen dehydroepiandrosterone (DHEA) peak in men and women in the third 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 17 -estradiol (E 2 ), 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 E 2 on cell proliferation and protein and/or gene expression of AR, prostate-specific antigen (PSA), IGF-I, IGF-I receptor (IGF-IR), IGF-II, IGF-binding proteins-2, -3, and -5, (IGFBPs-2, -3, and -5), and estrogen receptor- (ER ). Cell proliferation assays revealed significant stimulation by all four steroids. DHEA- and E 2 -induced responses were similar but delayed and reduced compared with that of T and DHT. All four hormones increased gene and/or protein expression of PSA, IGF-IR, IGF-I, and IGFBP-2 and decreased that of AR, ER , IGF-II, and IGFBP-3. There were no significant effects of hormone treatment on IGFBP-5 mRNA. DHEA and E 2 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. dehydroepiandrosterone; androgen receptor; prostate-specific antigen; insulin-like growth factor axis; estrogen receptor- ; lymph node-derived cancer of prostate Address for reprint requests and other correspondence: J. T. Arnold, Endocrine Section, LCI-NCCAM, NIH, 9 Memorial Dr., Rm 1N105, Bethesda, MD 20892-0933 (E-mail: jarnold{at}mail.nih.gov )