Dehydroepiandrosterone Administration or Gαq Overexpression Induces β-Catenin/T-Cell Factor Signaling and Growth via Increasing Association of Estrogen Receptor-β/Dishevelled2 in Androgen-Independent Prostate Cancer Cells

• Published in: Endocrinology (Philadelphia) 2010-04, Vol.151 (4), p.1428-1440
• Main Authors: Liu, Xunxian, Arnold, Julia T, Blackman, Marc R
• Format: Article
• Language: English
• Subjects: Androgen receptors; Androgens; Associations; Biological and medical sciences; c-Myc protein; Carcinogenesis; Carcinogens; Cell growth; Cyclin D1; D1 protein; Dehydroepiandrosterone; Dietary supplements; Dishevelled protein; Down-regulation; Estrogen receptors; Estrogens; Fundamental and applied biological sciences. Psychology; Gynecology. Andrology. Obstetrics; Lymphocytes T; Male genital diseases; Medical sciences; Myc protein; Nephrology. Urinary tract diseases; Prostate cancer; Protein expression; Proteins; Receptors; Signal transduction; siRNA; Transcription factors; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Vertebrates: endocrinology; Xenoestrogens; β-Catenin
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2009-0885

β-Catenin/T-cell factor signaling (β-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 β-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 β-CTS via increasing association of estrogen receptor (ER)-β 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 ERβ/Dvl2, protein expression of the β-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 Gα-subunits and DHEA down-regulation of ERβ/Dvl2 association. When Gαq is overexpressed in PC-3 cells, β-CTS is constitutively induced, including increasing c-Myc and cyclin D1 protein expression. This effect involved increasing associations of Gαq/Dvl2 and ERβ/Dvl2 and promoted cell growth. These activities require ERβ in DU-145 and PC-3 cells because they are blocked by ICI 182–780 treatment inactivating ERβ, small interfering RNA administration depleting ERβ, or AR overexpression arresting ERβ. These data suggest that novel pathways activating β-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. Dehydroepiandrosterone or Gαq increases β-CTS in androgen-independent PrCa cells.