Dehydroepiandrosterone administration or G{alpha}q overexpression induces {beta}-catenin/T-Cell factor signaling and growth via increasing association of estrogen receptor-{beta}/Dishevelled2 in androgen-independent prostate cancer cells.

beta-Catenin/T-cell factor signaling (beta-CTS) plays multiple critical roles in carcinogenesis and is blocked by androgens in androgen receptor (AR)-responsive prostate cancer (PrCa) cells, primarily via AR sequestration of beta-catenin from T-cell factor. Dehydroepiandrosterone (DHEA), often used as an over-the-counter nutritional supplement, is metabolized to androgens and estrogens in humans. The efficacy and safety of unregulated use of DHEA are unclear. We now report that DHEA induces beta-CTS via increasing association of estrogen receptor (ER)-beta with Dishevelled2 (Dvl2) in AR nonresponsive human PrCa DU145 cells, a line of androgen-independent PrCa (AiPC) cells. The induction is temporal, as assessed by measuring kinetics of the association of ERbeta/Dvl2, protein expression of the beta-CTS targeted genes, c-Myc and cyclin D1, and cell growth. However, in PC-3 cells, another human AiPC cell line, DHEA exerts no detectible effects, partly due to their lower expression of Galpha-subunits and DHEA down-regulation of ERbeta/Dvl2 association. When Galphaq is overexpressed in PC-3 cells, beta-CTS is constitutively induced, including increasing c-Myc and cyclin D1 protein expression. This effect involved increasing associations of Galphaq/Dvl2 and ERbeta/Dvl2 and promoted cell growth. These activities require ERbeta in DU-145 and PC-3 cells because they are blocked by ICI 182-780 treatment inactivating ERbeta, small interfering RNA administration depleting ERbeta, or AR overexpression arresting ERbeta. These data suggest that novel pathways activating beta-CTS play roles in the progression of AiPC. Although DHEA may enhance PrCa cell growth via androgenic or estrogenic pathways, the effects of DHEA administration on clinical prostate function remain to be determined.